Search

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-Text Revision diagnosis of GAD and 26 healthy comparison subjects were recruited and tested. The employed generalization paradigm consisted of quasi-randomly presented rings of gradually increasing size, with extreme sizes serving as conditioned danger cues (CS+) and conditioned safety cues. The rings of intermediary size served as generalization stimuli, creating a continuum of similarity between CS+ and conditioned safety cues across which to assess response slopes, referred to as generalization gradients. Primary outcome variables included slopes for fear-potentiated startle (electromyography) and self-reported risk ratings., Results: Behavioral and psychophysiological findings demonstrated 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., (Copyright © 2014 Society of Biological Psychiatry. All rights reserved.)

Background: Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in both explicit emotion regulation (EER) and top-down attentional control (TAC). Although studies have examined these processes in GSP or GAD, no work compares findings across the two disorders or examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of EER and TAC in GSP, GAD, and GSP/GAD., Methods: Medication-free adults with GSP (EER n = 19; TAC n = 18), GAD (EER n = 17; TAC n = 17), GSP/GAD (EER n = 17; TAC n = 15), and no psychopathology (EER n = 18; TAC n = 18) participated. During EER, individuals alternatively viewed and upregulated and downregulated responses to emotional pictures. During TAC, they performed an emotional Stroop task., Results: For both tasks, significant group × condition interactions emerged in dorsal anterior cingulate cortex 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 groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex and amygdala. This disorder-specific responding varied as a function of 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 TAC. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: We investigated whether performance on a reward processing task differs between fully remitted patients with major depressive disorder (MDD) and healthy control subjects after catecholamine depletion., Methods: Seventeen unmedicated subjects with remitted MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral alpha-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the reaction time on the monetary incentive delay (MID) task., Results: A diagnosis x drug interaction was evident (p = .001), which was attributable to an increase in reaction time across all incentive levels after AMPT in RMDD subjects (p = .001) but no significant AMPT effect on reaction time in control subjects (p = .17). There was no drug x diagnosis interaction on control tasks involving working memory or attention. In the RMDD sample the AMPT-induced depressive symptoms correlated with AMPT-induced changes in reaction time at all incentive levels of the MID task (r values = .58-.82, p < .002)., Conclusions: Under catecholamine depletion the RMDD subjects were robustly differentiated from control subjects by development of performance deficits on a reward processing task. These performance deficits correlated directly with the return of depressive symptoms after AMPT administration. The sensitivity of central reward processing systems to reductions in brain catecholamine levels thus seems to represent a trait-like marker in MDD.

Background: Positron emission tomography (PET) can localize and quantify neurokinin-1 (NK(1)) receptors in brain using the nonpeptide antagonist radioligand, [(18)F]SPA-RQ. We sought to determine if patients with panic disorder have altered density of NK(1) receptors in brain because of their history of recurrent panic attacks. We also sought to determine if a drug-induced panic attack releases substance P in brain, as measured by decreased binding of [(18)F]SPA-RQ., Methods: Positron emission tomography scans with [(18)F]SPA-RQ were performed in 14 patients with panic disorder and 14 healthy subjects. Of these two groups, 7 patients and 10 healthy subjects were scanned twice, once at baseline and once after injection of doxapram, a drug that induces panic attacks., Results: NK(1) receptor binding in patients (n = 14) compared with that in healthy subjects (n = 14) was significantly decreased by 12% to 21% in all brain regions. Doxapram effectively produced panic attacks in 6 of 7 patients with panic disorder but only 2 of 10 healthy subjects. Doxapram caused no significant change of [(18)F]SPA-RQ binding in either patients or healthy subjects., Conclusions: Although induction of a panic attack has no significant effect on [(18)F]SPA-RQ binding to NK(1) receptors, patients with panic disorder have widespread reduction of NK(1) receptor binding in brain.

Background: Panic disorder (PD) is hypothesized to be associated with altered function of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Previous proton magnetic resonance spectroscopy (MRS) studies found lower GABA concentrations in the occipital cortex of subjects with PD relative to healthy control subjects. The current study is the first MRS study to compare GABA concentrations between unmedicated PD subjects and control subjects in the prefrontal cortex (PFC)., Methods: Unmedicated subjects with PD (n = 17) and age- and sex-matched healthy control subjects (n = 17) were scanned on a 3 Tesla scanner using a transmit-receive head coil that provided a sufficiently homogenous radiofrequency field to obtain spectroscopic measurements in the dorsomedial/dorsal anterolateral and ventromedial areas of the PFC., Results: The prefrontal cortical GABA concentrations did not differ significantly between PD subjects and control subjects. There also was no statistically significant difference in glutamate/glutamine (Glx), choline, or N-acetyl aspartate concentrations., Conclusions: The previously reported finding of reduced GABA concentrations in the occipital cortex of PD subjects does not appear to extend to the PFC.

Background: It has been suggested that pharmacological challenges that induce panic attacks are confounded by effects of environmental stress, elevated baseline arousal, and expectancy bias., Methods: To control for effects of arousal and cognition on the panicogenic effects of pentagastrin, pharmacological challenges were conducted during sleep in seven patients with panic disorder or social phobia. All patients had previously experienced pentagastrin-induced panic while awake. Infusions of normal saline and pentagastrin (0.6 microg/kg) were administered in fixed order and timed so that pentagastrin infusions took place during the transition from Stage 2 to Stage 3 sleep. Long intravenous lines were placed for remote blood sampling and subsequent analysis of plasma adrenocorticotropic hormone and cortisol. Measures of anxiety and panic were obtained at baseline and upon awakening after pharmacological challenge., Results: All seven subjects awoke within seconds following pentagastrin infusion. Four patients reported symptoms that met criteria for panic. Neither baseline anxiety nor neuroendocrine measures were predictive of panic., Conclusions: These data demonstrate the ability to induce panic during a period of diminishing arousal and indicate that panic attacks can occur in the absence of elevated arousal and environmental stress.

The behavioral and neuroendocrine effects of meta-chlorophenylpiperazine (m-CPP), a serotonergic agonist, were compared with the effects of caffeine, an adenosine antagonist, in panic disorder patients. Patients with panic disorder were given single oral doses of 0.5 mg/kg m-CPP, 480 mg caffeine, and placebo on separate days under double-blind conditions. Both m-CPP and caffeine had significantly greater anxiogenic and panic-inducing effects than placebo, although caffeine produced nonsignificantly greater increases on all anxiety rating scales than m-CPP. Both m-CPP and caffeine produced significant equivalent increases in plasma cortisol concentrations, but only m-CPP produced plasma prolactin increases. These findings provide further evidence implicating both the serotonergic and adenosinergic receptor systems in the neurobiology of panic disorder.