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.
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).
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.
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.
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.
Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the ...degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder.
Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N=17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment.
The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder.
These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.
ABSTRACTBackgroundThe central nucleus of the amygdala and bed nucleus of the stria terminalis are involved primarily in phasic and sustained aversive states. Although both structures have been ...implicated in pathological anxiety, few studies with a clinical population have specifically focused on them, partly because of their small size. Previous work in our group used high-resolution imaging to map the resting-state functional connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in healthy subjects at 7 T, confirming and extending structural findings in humans and animals, while providing additional insight into cortical connectivity that is potentially unique to humans. MethodsIn the current follow-up study, we contrasted resting-state functional connectivity in the bed nucleus of the stria terminalis and central nucleus of the amygdala at 7 T between healthy volunteers ( n = 30) and patients with generalized and/or social anxiety disorder ( n = 30). ResultsResults revealed significant voxel-level group differences. Compared with healthy volunteers, patients showed stronger resting-state functional connectivity between the central nucleus of the amygdala and the lateral orbitofrontal cortex and superior temporal sulcus. They also showed weaker resting-state functional connectivity between the bed nucleus of the stria terminalis and the dorsolateral prefrontal cortex and occipital cortex. LimitationsThese findings depart from a previous report of resting-state functional connectivity in the central nucleus of the amygdala and bed nucleus of the stria terminalis under sustained threat of shock in healthy volunteers. ConclusionThis study provides functional MRI proxies of the functional dissociation of the bed nucleus of the stria terminalis and central nucleus of the amygdala, and suggests that resting-state functional connectivity of key structures in the processing of defensive responses do not recapitulate changes related to induced state anxiety. Future work needs to replicate and further probe the clinical significance of these findings.
Abstract Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an ...important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP ( n = 15) and age-, IQ-, and gender-matched comparison individuals ( n = 15) read 1st (e.g., I'm ugly ), and 2nd (e.g., You're ugly ) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others.
While social phobia in adolescence predicts the illness in adulthood, no study has directly compared the neural responses in social phobia in adults and adolescents. The authors examined neural ...responses to facial expressions in adults and adolescents with social phobia to determine whether the neural correlates of adult social phobia during face processing also manifest in adolescent social phobia.
Blood-oxygen-level-dependent (BOLD) responses were compared in 39 medication-free participants with social phobia (25 adults and 14 adolescents) and 39 healthy comparison subjects (23 adults and 16 adolescents) matched on age, IQ, and gender. During fMRI scans, participants saw angry, fearful, and neutral expression stimuli while making a gender judgment.
Significant diagnosis-by-emotion interactions were observed within the amygdala and the rostral anterior cingulate cortex, as has previously been hypothesized. In these regions, both the adolescent and adult social phobia patients showed significantly increased BOLD responses relative to their respective age-matched comparison subjects, and there was no evidence of age-related modulation of between-group differences. These enhanced responses occurred specifically when viewing angry (rostral anterior cingulate cortex) and fearful (amygdala and rostral anterior cingulate cortex) expressions but not when viewing neutral expressions. In addition, the severity of social phobia was significantly correlated with the enhanced rostral anterior cingulate cortex response in the adults.
The neural correlates of adult social phobia during face processing also manifest in adolescents. Neural correlates that are observed in adult social phobia may represent the persistence of profiles established earlier in life rather than adaptive responses to such earlier perturbations or maturational changes. These cross-sectional observations might encourage longitudinal fMRI studies of adolescent social phobia.
Little is known about the neural underpinnings of generalized social phobia, which is defined by a persistent heightened fear of social disapproval. Using event-related functional MRI (fMRI), the ...authors examined whether the intent of an event, which mediates the neural response to social disapproval in healthy individuals, differentially affects response in generalized social phobia.
Sixteen patients with generalized social phobia and 16 healthy comparison subjects group-matched on age, gender, and IQ underwent fMRI scans while reading stories that involved neutral social events, unintentional social transgressions (e.g., choking on food at a party and coughing it up), or intentional social transgressions (e.g., disliking food at a party and spitting it out).
Significant group-by-transgression interactions were observed in ventral regions of the medial prefrontal cortex. Healthy individuals tended to show increased blood-oxygen-level-dependent responses to intentional relative to unintentional transgressions. Patients with generalized social phobia, however, showed significantly increased responses to the unintentional transgressions. They also rated the unintentional transgressions as significantly more embarrassing than did the comparison subjects. Results also revealed significant group main effects in the amygdala and insula bilaterally, reflecting elevated generalized social phobia responses in these regions to all event types.
These results further implicate the medial prefrontal cortex in the pathophysiology of generalized social phobia, specifically through its involvement in distorted self-referential processing. These results also further underscore the extended role of the amygdala and insula in the processing of social stimuli more generally in generalized social phobia.
The goal of clinical and translational science (CTS) is to fill gaps in medical knowledge toward improving human health. However, one of our most pressing challenges does not reside within the ...biological map we navigate to find sustainable cures but rather the moral compass to recognize and overcome racial and ethnic injustices that continue to influence our society and hinder diverse research rigor. The Georgetown-Howard Universities Center for Clinical and Translational Science includes an inter-institutional TL1-funded training program for predoctoral/postdoctoral trainees in Translational Biomedical Science (TBS).
In the fall of 2020, the TBS program responded to the national social justice crisis by incorporating a curriculum focused on structural racism in biomedical research. Educational platforms, including movie reviews, Journal Clubs, and other workshops, were threaded throughout the curriculum by ensuring safe spaces to discuss racial and ethnic injustices and providing trainees with practical steps to recognize, approach, and respond to these harmful biases in the CTS. Workshops also focused on why individuals underrepresented in science are vital for addressing and closing gaps in CTS.
Paring analysis using REDCap software de-identified participants after invitations were sent and collected in the system to maintain anonymity for pre- and post-analysis. The Likert scale evaluated respondents' understanding of diverse scientific circumstances. The pre/Fall and post/Spring surveys suggested this curriculum was successful at raising institutional awareness of racial and ethnic biases. Evaluating the effectiveness of our program with other training Clinical and Translational Science Awards (CTSA) consortiums will strengthen both the academic and professional TBS programs.
The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded ('pseudopheochromocytoma') usually remain unclear. Blood pressure disturbances and symptoms of ...catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma.
Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine.
Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P < 0.05) baseline plasma concentrations of epinephrine, 80% higher (P < 0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P < 0.05) increases in plasma epinephrine after glucagon. Adrenal 18F-fluorodopamine-derived radioactivity did not differ between groups. Compared with changes in plasma norepinephrine, falls in blood pressure after trimethaphan were 13-fold larger (P < 0.005) and increases in blood pressure after yohimbine were threefold larger (P < 0.01) in pseudopheochromocytoma patients than in controls.
Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.
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