Resting-state connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in clinical anxiety

Background: The 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 restingstate 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. Methods: In 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). Results: Results 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. Limitations: These 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. Conclusion: This 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.

Using a shared governance structure to evaluate the implementation of a new model of care: the shared experience of a performance improvement committee.

Sustaining change in the behaviors and habits of experienced practicing nurses can be frustrating and daunting, even when changes are based on evidence. Partnering with an active shared governance structure to communicate change and elicit feedback is an established method to foster partnership, equity, accountability, and ownership. Few recent exemplars in the literature link shared governance, change management, and evidence-based practice to transitions in care models. This article describes an innovative staff-driven approach used by nurses in a shared governance performance improvement committee to use evidence-based practice in determining the best methods to evaluate the implementation of a new model of care.

Educational initiative in an NCATS TL1 training program to address the impact of systemic racism on human health, biomedical research, and the translational scientist.

Introduction: 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). Methods: 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. Results: 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.

Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia.

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.

Repetitive TMS combined with exposure therapy for PTSD: a preliminary study.

Treatment for anxiety and post-traumatic stress disorder (PTSD) includes exposure therapy and medications, but some patients are refractory. Few studies of repetitive transcranial magnetic stimulation (rTMS) for anxiety or PTSD exist. In this preliminary report, rTMS was combined with exposure therapy for PTSD. Nine subjects with chronic, treatment-refractory PTSD were studied in a placebo-controlled, crossover design of imaginal exposure therapy with rTMS (1Hz) versus sham. PTSD symptoms, serum and 24h urine were obtained and analyzed. Effect sizes for PTSD symptoms were determined using Cohen's d. Active rTMS showed a larger effect size of improvement for hyperarousal symptoms compared to sham; 24-h urinary norepinephrine and serum T4 increased; serum prolactin decreased. Active rTMS with exposure may have symptomatic and physiological effects. Larger studies are needed to confirm these preliminary findings and verify whether rTMS plus exposure therapy has a role in the treatment of PTSD.

Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression.

BACKGROUND: Neuropeptide Y (NPY) and serotonergic systems have been implicated in the pathophysiology of depression but have not yet been linked together. METHODS: In a randomized, double-blind crossover study, 28 medication-free patients with remitted depression and 26 healthy control subjects underwent tryptophan depletion (TD) and sham depletion. Plasma NPY concentrations were determined at baseline and at +5, +7, and +24 h during TD and sham depletion, respectively. Hamilton Depression Rating Scale (HDRS, 24-item) scores were assessed at baseline and at +7 and +24 h after TD and sham depletion, respectively. RESULTS: There was no difference between healthy subjects and patients with remitted depression in baseline plasma NPY concentrations and in plasma NPY concentrations during TD and sham depletion, respectively. Plasma NPY concentrations did not differ between TD and sham depletion. At no time point there was an association between HDRS scores and plasma NPY concentrations in patients with remitted depression. LIMITATIONS: Plasma NPY concentrations in rMDD patients were not obtained during the symptomatic phase of the illness. Only peripheral measurements of NPY were used. CONCLUSIONS: Decreased plasma NPY concentrations, as described previously during a spontaneous episode of major depression, appear as state but not as trait marker in depression. No evidence was found for an involvement of plasma NPY in relapse during TD. There appears no direct functional link between serotonergic neurotransmission and plasma NPY concentrations.

Association between level of emotional intelligence and severity of anxiety in generalized social phobia.

Generalized social phobia (GSP) is characterized by a marked fear of most social situations. It is associated with an anomalous neural response to emotional stimuli, and individuals with the disorder frequently show interpretation bias in social situations. From this it might be suggested that GSP involves difficulty in accurately perceiving, using, understanding and managing emotions. Here we applied the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) to medication-free GSP (n=28) and no pathology (n=21) individuals. Patients with GSP performed within the normal range on the measure however severity of social anxiety significantly correlated with emotional intelligence (EI). Specifically, there was a negative correlation between social anxiety severity and Experiential (basic-level emotional processing) EI. In contrast, there was no significant correlation between social anxiety severity and Strategic (higher-level conscious emotional processing) EI. These results suggest that EI may index emotional processing systems that mitigate the impact of systems causally implicated in GSP.

Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Distinct responses to predictable and unpredictable threat in anxiety pathologies: effect of panic attack.

BACKGROUND: Delineating specific clinical phenotypes of anxiety disorders is a crucial step toward better classification and understanding of these conditions. The present study sought to identify differential aversive responses to predictable and unpredictable threat of shock in healthy comparisons and in non-medicated anxiety patients with and without a history of panic attacks (PAs). METHOD: 143 adults (72 healthy controls; 71 patients with generalized anxiety disorder (GAD) or/and social anxiety disorder (SAD), 24 with and 47 without PAs) were exposed to three conditions: 1) predictable shocks signaled by a cue, 2) unpredictable shocks, and 3) no shock. Startle magnitude was used to assess aversive responses. RESULTS: Across disorders, a PA history was specifically associated with hypersensitivity to unpredictable threat. By disorder, SAD was associated with hypersensitivity to predictable threat, whereas GAD was associated with exaggerated baseline startle. CONCLUSIONS: These results identified three physiological patterns. The first is hypersensitivity to unpredictable threat in individuals with PAs. The second is hypersensitivity to predictable threat, which characterizes SAD. The third is enhanced baseline startle in GAD, which may reflect propensity for self-generated anxious thoughts in the absence of imminent danger. These results inform current thinking by linking specific clinical features to particular physiology profiles.

Prediction Error Representation in Individuals With Generalized Anxiety Disorder During Passive Avoidance.

OBJECTIVE: Deficits in reinforcement-based decision making have been reported in generalized anxiety disorder. However, the pathophysiology of these deficits is largely unknown; published studies have mainly examined adolescents, and the integrity of core functional processes underpinning decision making remains undetermined. In particular, it is unclear whether the representation of reinforcement prediction error (PE) (the difference between received and expected reinforcement) is disrupted in generalized anxiety disorder. This study addresses these issues in adults with the disorder. METHOD: Forty-six unmedicated individuals with generalized anxiety disorder and 32 healthy comparison subjects group-matched on IQ, gender, and age performed a passive avoidance task while undergoing functional MRI. Data analyses were performed using a computational modeling approach. RESULTS: Behaviorally, individuals with generalized anxiety disorder showed impaired reinforcement-based decision making. Imaging results revealed that during feedback, individuals with generalized anxiety disorder relative to healthy subjects showed a reduced correlation between PE and activity within the ventromedial prefrontal cortex, ventral striatum, and other structures implicated in decision making. In addition, individuals with generalized anxiety disorder relative to healthy participants showed a reduced correlation between punishment PEs, but not reward PEs, and activity within the left and right lentiform nucleus/putamen. CONCLUSIONS: This is the first study to identify computational impairments during decision making in generalized anxiety disorder. PE signaling is significantly disrupted in individuals with the disorder and may lead to their decision-making deficits and excessive worry about everyday problems by disrupting the online updating ("reality check") of the current relationship between the expected values of current response options and the actual received rewards and punishments.

Differential performance on tasks of affective processing and decision-making in patients with Panic Disorder and Panic Disorder with comorbid Major Depressive Disorder.

BACKGROUND: Neuropsychological studies have provided evidence for deficits in psychiatric disorders, such as schizophrenia and mood disorders. However, neuropsychological function in Panic Disorder (PD) or PD with a comorbid diagnosis of Major Depressive Disorder (MDD) has not been comprehensively studied. The present study investigated neuropsychological functioning in patients with PD and PD + MDD by focusing on tasks that assess attention, psychomotor speed, executive function, decision-making, and affective processing. METHODS: Twenty-two unmedicated patients with PD, eleven of whom had a secondary diagnosis of MDD, were compared to twenty-two healthy controls, matched for gender, age, and intelligence on tasks of attention, memory, psychomotor speed, executive function, decision-making, and affective processing from the Cambridge Neuropsychological Test Automated Battery (CANTAB), Cambridge Gamble Task, and Affective Go/No-go Task. RESULTS: Relative to matched healthy controls, patients with PD + MDD displayed an attentional bias toward negatively-valenced verbal stimuli (Affective Go/No-go Task) and longer decision-making latencies (Cambridge Gamble Task). Furthermore, the PD + MDD group committed more errors on a task of memory and visual discrimination compared to their controls. In contrast, no group differences were found for PD patients relative to matched control subjects. LIMITATIONS: The sample size was limited, however, all patients were drug-free at the time of testing. CONCLUSIONS: The PD + MDD patients demonstrated deficits on a task involving visual discrimination and working memory, and an attentional bias towards negatively-valenced stimuli. In addition, patients with comorbid depression provided qualitatively different responses in the areas of affective and decision-making processes.

Abnormal decision-making in generalized anxiety disorder: Aversion of risk or stimulus-reinforcement impairment?

There is preliminary data indicating that patients with generalized anxiety disorder (GAD) show impairment on decision-making tasks requiring the appropriate representation of reinforcement value. The current study aimed to extend this literature using the passive avoidance (PA) learning task, where the participant has to learn to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Six stimuli engendering reward and six engendering punishment are presented once per block for 10 blocks of trials. Thirty-nine medication-free patients with GAD and 29 age-, IQ and gender matched healthy comparison individuals performed the task. In addition, indexes of social functioning as assessed by the Global Assessment of Functioning (GAF) scale were obtained to allow for correlational analyzes of potential relations between cognitive and social impairments. The results revealed a Group-by-Error Type-by-Block interaction; patients with GAD committed significantly more commission (passive avoidance) errors than comparison individuals in the later blocks (blocks 7,8, and 9). In addition, the extent of impairment on these blocks was associated with their functional impairment as measured by the GAF scale. These results link GAD with anomalous decision-making and indicate that a potential problem in reinforcement representation may contribute to the severity of expression of their disorder.

Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls.

CONTEXT: An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder (MDD) is the response to tryptophan depletion (TD) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan. OBJECTIVE: To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD. DESIGN: Randomized double-blind crossover study. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with remitted MDD (18 women and 9 men; mean +/- SD age, 39.8 +/- 12.7 years) and 19 controls (10 women and 9 men; mean +/- SD age, 34.4 +/- 11.5 years). INTERVENTIONS: We induced TD by administering capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing hydrous lactose. Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD. Magnetic resonance images were obtained for all participants. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD. Behavioral assessments used a modified (24-item) version of the Hamilton Depression Rating Scale. RESULTS: Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls (P<.001). Compared with sham depletion, TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex, medial thalamus, anterior and posterior cingulate cortices, and ventral striatum in patients with remitted MDD but not in controls. CONCLUSION: 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.

Pentagastrin-induced sleep panic attacks: panic in the absence of elevated baseline arousal.

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.

Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear.

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.

Reduced dorsal anterior cingulate cortical activity during emotional regulation and top-down attentional control in generalized social phobia, generalized anxiety disorder, and comorbid generalized social phobia/generalized anxiety 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.

Avoidant coping in panic disorder: a yohimbine biological challenge study.

Few studies have addressed whether the use of avoidance-oriented coping strategies is related to the development of panic in patients with panic disorder(PD). Self-report, clinician-rated, and physiological data were collected from 42 individuals who participated in a yohimbine biological challenge study, performed under double-blind, placebo-controlled conditions. Participants included 20 healthy controls and 22 currently symptomatic patients who met DSM-IV-TR diagnostic criteria for PD. Consistent with prediction, patients with PD who had higher perceived efficacy of avoidance-oriented strategies in reducing anxiety-related thoughts reported increased severity in panic symptoms during the yohimbine challenge condition as compared to the placebo. Further, patients with PD who had more fear of cognitive dyscontrol, cardiovascular symptoms, and publicly observable anxiety also reported increased severity in panic symptoms during the challenge. Healthy controls who had more fear of cardiovascular symptoms similarly reported increased severity in panic symptoms during the challenge. No effects were found for heart rate response to the challenge agent. These results provide support for the role of avoidance-oriented coping strategies and fear of anxiety-related symptoms as risk and maintenance factors in the development of panic symptoms, particularly within a biological challenge model.

The pathology of social phobia is independent of developmental changes in face processing.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Overgeneralization of conditioned fear as a pathogenic marker of panic disorder.

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.

Social norm processing in adult social phobia: atypically increased ventromedial frontal cortex responsiveness to unintentional (embarrassing) transgressions.

OBJECTIVE: 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. METHOD: 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). RESULTS: 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. CONCLUSIONS: 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.