Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.

INTRODUCTION: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. METHOD: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. RESULTS: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). DISCUSSION: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Association of rs7688285 allelic variation coding for GLRB with fear reactivity and exposure-based therapy in patients with panic disorder and agoraphobia.

The gene coding for glycine receptor ß subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk¼) in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.

Incongruence Between Implicit Attachment Schemes and Unconscious Attachment Representations.

Assessments based on reaction time and language-based interviews postulate that unconscious attachment processes be measured. Nevertheless, a possible empirical equivalence of these two approaches has not yet been investigated. To fill this void, the Adult Attachment Interview and the Implicit Association Test were implemented with a group of patients with panic disorder (n = 157, mean age = 29, SD = 2.47) based on the Structured Clinical Interview for DSM-IV, axis I and II disorders and a group of healthy individuals (n = 138). In total, the securely attached individuals showed significantly more positive attitudes toward their mother than the insecurely attached individuals. In the healthy individuals, the secure and disorganized classifications showed significantly more positive attitudes toward the mother in comparison with the insecure attachment classification, as well as the patient group. In summary, implicit attachment patterns based on reaction times are not equivalent to an attachment representation based on language markers. For the disorganized attachment representation, no differences were present between the information processing of the memory/association network and the autobiographic memory function.

Heart rate variability in patients with agoraphobia with or without panic disorder remains stable during CBT but increases following in-vivo exposure.

Patients with anxiety disorders have a lower heart rate variability (HRV) than healthy controls. Low HRV is associated with cardiovascular disease and dysfunction of the autonomic nervous system (ANS). The aim of the present study was to investigate if HRV in patients with agoraphobia with or without panic disorder can be influenced by cognitive behavioral therapy (CBT). 73 patients with agoraphobia with or without panic disorder were included in the study. Heart rate (HR) and HRV were recorded at rest before and after CBT and during in-vivo exposure. No changes in HR and HRV were observed throughout therapy. During in-vivo exposure HRV increased significantly and HR exhibited a tendency to decrease. Despite clinical improvement of anxiety symptoms, ANS activity at rest did not seem to be influenced by CBT. However, during in-vivo exposure, HRV changed significantly, indicating a higher parasympathetic activity at the end of exposure.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

The impact of depressive comorbidity on neural plasticity following cognitive-behavioral therapy in panic disorder with agoraphobia.

BACKGROUND: Depressive disorders are a frequent comorbidity of panic disorder with agoraphobia (PD/AG). Cognitive-behavioral therapy (CBT) for PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbidities. However, as depressive comorbidities can confound fear circuitry activation (i.e. amygdalae, insulae, anterior cingulate cortex) in PD/AG, we investigated whether comorbid depressive disorders alter neural plasticity following CBT. METHODS: Within a randomized, controlled clinical trial on exposure-based CBT, forty-two PD/AG patients including fifteen (35.7%) with a comorbid depressive disorder (PD/AG + DEP) participated in a longitudinal functional magnetic resonance imaging (fMRI) study. A differential fear conditioning task was used as probe of interest. A generalized psycho-physiological interaction analysis (gPPI) served to study functional connectivity patterns. RESULTS: After CBT, only PD/AG patients without comorbid depressive disorders (PD/AG-DEP) showed reduced activation in the left inferior frontal gyrus (IFG) extending to the insula. While PD/AG-DEP patients showed enhanced functional connectivity (FC) between the left IFG and subcortical structures (anterior cingulate cortex, thalamus and midbrain), PD/AG + DEP patients exhibited increased FC between the left IFG and cortical structures (prefrontal, parietal regions). In both groups, FC decreased following CBT. LIMITATIONS: Primary depressed and medicated patients were excluded. Major depression and dysthymia were collapsed. CONCLUSIONS: Reduced activation in the left IFG, as previously shown in PD/AG, appears to be a specific substrate of CBT effects in PD/AG-DEP patients only. Differential patterns of FC pertaining to fear circuitry networks in patients without depression vs. cognitive networks in patients with comorbid depression may point towards different pathways recruited by CBT as a function of comorbidity.

Associations of plasma testosterone with clinical manifestations in acute panic disorder.

The probable implication of testosterone in the neurobiology of anxiety disorders, and particularly panic disorder (PD), is poorly studied. We explored for potential differences concerning testosterone (T) plasma levels and the ratio testosterone/cortisol (T/C) between medication-free, consecutively-referred patients with acute exacerbation of PD comorbid with agoraphobia (PDA) (N = 40; females = 24; age = 31.4 ± 7.1 years) and healthy controls (N = 80; females = 48; matched for age). Moreover, we investigated for potential associations of T levels and T/C ratio with the severity of acute PDA psychopathology in the patients of the sample. Psychometric measures included panic attacks' number during last three weeks (PA-21days), the Agoraphobic Cognitions Questionnaire (ACQ) and the Hamilton Anxiety Rating Scale (HARS). Male patients -but not female ones- demonstrated significantly lower T levels compared to controls. Moreover, in male patients, a significant inverse association emerged between T/C ratio and PA-21days, so that lower T/C ratio is associated with significantly more panic attacks. On the contrary, female patients demonstrated significant positive associations: (a) between T levels and PDA-related pathological cognitions (ACQ); (b) between the T/C ratio and both PA-21days and anxiety symptoms' severity (HARS). The results of the study suggest that testosterone is significantly associated to the severity of clinical manifestations of acute panic disorder, although in a different fashion concerning the two genders.

Anxiety disorders and figural fluency: A measure of executive function.

BACKGROUND: Anxiety possibly interferes with executive functioning, although most studies rely on anxiety symptoms or lack control for comorbid depression. The objective of the present study is to examine the association between executive functioning and (individual) anxiety disorders with ak,ld without controlling for depression. METHOD: Generalized anxiety disorder (GAD), panic disorder with and without agoraphobia, agoraphobia, social phobia, as well as depressive disorder according to DSM-IV criteria were assessed with the Mini International Neuropsychiatric Interview in 82,360 community-dwelling people participating in the Lifelines cohort. Figural fluency as a measure of executive functioning was assessed with the Ruff Figural Fluency Test (RFTT). Linear regression analyses with the RFFT score as the dependent variable and psychiatric diagnosis as independent variables (dummies) were performed, adjusted for potential confounders. Multivariate results are presented with and without adjustment for depression. RESULTS: Presence of any anxiety disorder was associated with worse performance on the RFFT (B = - 0.78, SE = 0.32, p = .015), independent of depression. No dose-response relationship with the number of anxiety disorders was found. Only agoraphobia and generalized anxiety disorder were significantly associated with the RFFT score in the multivariate models. Agoraphobia remained significant when further adjusted for depressive disorder (B = - 1.14, SE = 0.41, p < .01), while GAD did not (B = 0.013, SE = 0.431, p = .975). LIMITATIONS: Executive function was tested by only one measure, namely figural fluency. CONCLUSION: Agoraphobia is associated with worse executive functioning. Treatment of agoraphobia could be influenced by the executive dysfunction which clinicians should be aware of when regular treatment fails.

Face Perception in Social Anxiety: Visuocortical Dynamics Reveal Propensities for Hypervigilance or Avoidance.

BACKGROUND: Theories of aberrant attentional processing in social anxiety, and anxiety disorders more broadly, have postulated an initial hypervigilance or facilitation to clinically relevant threats and consequent defensive avoidance. However, existing objective measurements utilized to explore this phenomenon lack the resolution to elucidate attentional dynamics, particularly covert influences. METHODS: We utilized a continuous measure of visuocortical engagement, the steady-state visual evoked potential in response to naturalistic angry, fearful, happy, and neutral facial expressions. Participants were treatment-seeking patients with principal diagnoses of social anxiety circumscribed to performance situations (n = 21) or generalized across interaction contexts (n = 42), treatment-seeking patients with panic disorder with agoraphobia (n = 25), and 17 healthy participants. RESULTS: At the principal disorder level, only circumscribed social anxiety patients showed sustained visuocortical facilitation to aversive facial expressions. Control participants as well as patients with panic disorder with agoraphobia and generalized social anxiety showed no bias. More finely stratifying the sample according to clinical judgment of social anxiety severity and interference revealed a linear increase in visuocortical bias to aversive expressions for all but the most severely impaired patients. This group showed an opposing sustained attentional disengagement. CONCLUSIONS: Rather than shifts between covert vigilance and avoidance of aversive facial expressions, social anxiety appears to confer a sustained bias for one or the other. While vigilant attention reliably increases with social anxiety severity for the majority of patients, the most impaired patients show an opposing avoidance. These distinct patterns of attentional allocation could provide a powerful means of personalizing neuroscience-based interventions to modify attention bias and related impairment.

Neurobiological and clinical effects of fNIRS-controlled rTMS in patients with panic disorder/agoraphobia during cognitive-behavioural therapy.

BACKGROUND: A relevant proportion of patients with panic disorder (PD) does not improve even though they receive state of the art treatment for anxiety disorders such as cognitive-behavioural therapy (CBT). At the same time, it is known, that from a neurobiological point of view, PD patients are often characterised by prefrontal hypoactivation. Intermittent Theta Burst Stimulation (iTBS) is a non-invasive type of neurostimulation which can modulate cortical activity and thus has the potential to normalise prefrontal hypoactivity found in PD. We therefore aimed at investigating the effects of iTBS as an innovative add-on to CBT in the treatment for PD. METHODS: In this double-blind, bicentric study, 44 PD patients, randomised to sham or verum stimulation, received 15 sessions of iTBS over the left prefrontal cortex (PFC) in addition to 9 weeks of group CBT. Cortical activity during a cognitive as well as an emotional (Emotional Stroop) paradigm was assessed both at baseline and post-iTBS treatment using functional near-infrared spectroscopy (fNIRS) and compared to healthy controls. RESULTS: In this manuscript we only report the results of the emotional paradigm; for the results of the cognitive paradigm please refer to Deppermann et al. (2014). During the Emotional Stroop test, PD patients showed significantly reduced activation to panic-related compared to neutral stimuli for the left PFC at baseline. Bilateral prefrontal activation for panic-related stimuli significantly increased after verum iTBS only. Clinical ratings significantly improved during CBT and remained stable at follow-up. However, no clinical differences between the verum- and sham-stimulated group were identified, except for a more stable reduction of agoraphobic avoidance during follow-up in the verum iTBS group. LIMITATIONS: Limitations include insufficient blinding, the missing control for possible state-dependent iTBS effects, and the timing of iTBS application during CBT. CONCLUSION: Prefrontal hypoactivity in PD patients was normalised by add-on iTBS. Clinical improvement of anxiety symptoms was not affected by iTBS.

Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice.

Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2-/-) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph+/-) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.

Internal Structure and Clinical Utility of the Anxiety Control Questionnaire-Revised (ACQ-R) Spanish Version.

Perceived control has shown predictive value for anxiety severity symptoms as well as cognitive-behavior therapy outcomes. The most commonly used measure of perceived control is the Anxiety Control Questionnaire (ACQ), and more recently the ACQ Revised (ACQ-R). However, both questionnaires have shown structural inconsistencies among several studies. Also, although the ACQ and ACQ-R seem to be multidimensional instruments, a single total score have been commonly used. This study examined the internal structure of the ACQ-R Spanish version using exploratory factor and exploratory bi-factor analysis in a sample of 382 college students and 52 people diagnosed of panic disorder (with or without agoraphobia). Also, in this study we assessed the preliminary diagnostic value of the ACQ-R scores. The results indicated that the ACQ-R Spanish version structure consisted of two factors: one related with perceived control of internal emotional reactions (Emotion Control) and another related with perceived control of external events (Threat and Stress Control). Both specific factors can be adequately summarized by a general factor (General Anxiety Perception of Control; CFI = .973, TLI = .954, RMSEA = .039; p = .002), which accounted for 70% of the common explained variance. The correlations between the ACQ-R scores and with variables like anxiety (r = -.66) or anxiety sensitivity (r = -.50) presented the expected pattern of results. Either the two dimensions structure or the total score have proved to be a good tool to distinguish between participants with panic disorder and non-clinical samples (area under the curve = 0.79).

Casting wider nets for anxiety and depression: disability-driven cross-diagnostic subtypes in a large cohort.

BACKGROUND: In search of empirical classifications of depression and anxiety, most subtyping studies focus solely on symptoms and do so within a single disorder. This study aimed to identify and validate cross-diagnostic subtypes by simultaneously considering symptoms of depression and anxiety, and disability measures. METHOD: A large cohort of adults (Lifelines, n = 73 403) had a full assessment of 16 symptoms of mood and anxiety disorders, and measurement of physical, social and occupational disability. The best-fitting subtyping model was identified by comparing different hybrid mixture models with and without disability covariates on fit criteria in an independent test sample. The best model's classes were compared across a range of external variables. RESULTS: The best-fitting Mixed Measurement Item Response Theory model with disability covariates identified five classes. Accounting for disability improved differentiation between people reporting isolated non-specific symptoms ['Somatic' (13.0%), and 'Worried' (14.0%)] and psychopathological symptoms ['Subclinical' (8.8%), and 'Clinical' (3.3%)]. Classes showed distinct associations with clinically relevant external variables [e.g. somatization: odds ratio (OR) 8.1-12.3, and chronic stress: OR 3.7-4.4]. The Subclinical class reported symptomatology at subthreshold levels while experiencing disability. No pure depression or anxiety, but only mixed classes were found. CONCLUSIONS: An empirical classification model, incorporating both symptoms and disability identified clearly distinct cross-diagnostic subtypes, indicating that diagnostic nets should be cast wider than current phenomenology-based categorical systems.

A Human Open Field Test Reveals Thigmotaxis Related to Agoraphobic Fear.

BACKGROUND: Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia. METHODS: A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. RESULTS: Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia. CONCLUSIONS: This study is the first to our knowledge to verify the translational validity of the OFT and to reveal that thigmotaxis, an evolutionarily adaptive behavior shown by most species, is related to agoraphobia, a pathologic fear of open spaces, and anxiety sensitivity, a risk factor for agoraphobia.

Panic disorder with agoraphobia from a behavioral neuroscience perspective: Applying the research principles formulated by the Research Domain Criteria (RDoC) initiative.

In the current review, we reconceptualize a categorical diagnosis-panic disorder and agoraphobia-in terms of two constructs within the domain "negative valence systems" suggested by the Research Domain Criteria initiative. Panic attacks are considered as abrupt and intense fear responses to acute threat arising from inside the body, while anxious apprehension refers to anxiety responses to potential harm and more distant or uncertain threat. Taking a dimensional view, panic disorder with agoraphobia is defined with the threat-imminence model stating that defensive responses are dynamically organized along the dimension of the proximity of the threat. We tested this model within a large group of patients with panic disorder and agoraphobia (N = 369 and N = 124 in a replication sample) and found evidence that panic attacks are indeed instances of circa strike defense. This component of the defensive reactivity was related to genetic modulators within the serotonergic system. In contrast, anxious apprehension-characterized by attentive freezing during postencounter defense-was related to general distress and depressive mood, as well as to genetic modulations within the hypothalamic-pituitary-adrenal (HPA) axis. Patients with a strong behavioral tendency for active and passive avoidance responded better to exposure treatment if the therapist guides the patient through the exposure exercises.

Metabolic decoupling in daily life in patients with panic disorder and agoraphobia.

Various studies have assessed autonomic and respiratory underpinnings of panic attacks, yet the psychophysiological functioning of panic disorder (PD) patients has rarely been examined under naturalistic conditions at times when acute attacks were not reported. We hypothesized that emotional activation in daily life causes physiologically demonstrable deviations from efficient metabolic regulation in PD patients. Metabolic coupling was estimated as within-individual correlations between heart rate (HR) and indices of metabolic activity, i.e., physical activity (measured by 3-axial accelerometry, Acc), and minute ventilation (Vm, measured by calibrated inductive plethysmography, as proxy for oxygen consumption). A total of 565 daytime hours were recorded in 19 PD patients and 20 healthy controls (HC). Pairwise cross-correlations of minute-by-minute averages of these metabolic indices were calculated for each participant and then correlated with several indices of self-reported anxiety. Ambulatory HR was elevated in PD (p = .05, d = 0.67). Patients showed reduced HR-Acc (p < .006, d = 0.97) and HR-Vm coupling (p < .009, d = 0.91). Combining Vm and Acc to predict HR showed the strongest group separation (p < .002, d = 1.07). Discriminant analyses, based on the combination of Vm and Acc to predict HR, classified 77% of all participants correctly. In PD, HR-Acc coupling was inversely related to trait anxiety sensitivity, as well as tonic and phasic daytime anxiety. The novel method that was used demonstrates that anxiety in PD may reduce efficient long-term metabolic coupling. Metabolic decoupling may serve as physiological characteristic of PD and might aid diagnostics for PD and other anxiety disorders. This measure deserves further study in research on health consequences of anxiety and psychosocial stress.

Neural correlates of anxiety sensitivity in panic disorder: A functional magnetic resonance imaging study.

Panic disorder has been associated with dysfunctional neuropsychological dimensions, including anxiety sensitivity. Brain-imaging studies of the neural correlates of emotional processing have identified a network of structures that constitute the neural circuitry for emotions. The anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC) and insula, which are part of this network, are also involved in the processing of threat-related stimuli. The aim of the study was to investigate if neural activity in response to emotional stimuli in the cortico-limbic network is associated to anxiety sensitivity in panic disorder. In a sample of 18 outpatients with panic disorder, we studied neural correlates of implicit emotional processing of facial affect expressions with a face-matching paradigm; correlational analyses were performed between brain activations and anxiety sensitivity. The correlational analyses performed showed a positive correlation between anxiety sensitivity and brain activity during emotional processing in regions encompassing the PFC, ACC and insula. Our data seem to confirm that anxiety sensitivity is an important component of panic disorder. Accordingly, the neural underpinnings of anxiety sensitivity could be an interesting focus for treatment and further research.

Frontal cortex absolute beta power measurement in Panic Disorder with Agoraphobia patients.

UNLABELLED: Panic disorder patients are hypervigilant to danger cues and highly sensitive to unpredictable aversive events, what leads to anticipatory anxiety, that is one key component of the disorder maintenance. Prefrontal cortex seems to be involved in these processes and beta band activity may be related to the involvement of top-down processing, whose function is supposed to be disrupted in pathological anxiety. The objective of this study was to measure frontal absolute beta-power (ABP) with qEEG in panic disorder and agoraphobia (PDA) patients compared to healthy controls. METHODS: qEEG data were acquired while participants (24 PDA patients and 21 controls) watched a computer simulation (CS), consisting of moments classified as "high anxiety" (HAM) and "low anxiety" (LAM). qEEG data were also acquired during two rest conditions, before and after the computer simulation display. The statistical analysis was performed by means of a repeated measure analysis of variance (two-way ANOVA) and ABP was the dependent variable of interest. The main hypothesis was that a higher ABP in PDA patients would be found related to controls. Moreover, in HAM the ABP would be different than in LAM. RESULTS: the main finding was an interaction between the moment and group for the electrodes F7, F8, Fp1 and Fp2. We observed a higher ABP in PDA patients when compared to controls while watching the CS. The higher beta-power in the frontal cortex for the PDA group may reflect a state of high excitability, together with anticipatory anxiety and maintenance of hypervigilant cognitive state. CONCLUSIONS: our results suggest a possible deficiency in top-down processing reflected by a higher ABP in the PDA group while watching the CS and they highlight the recruitment of prefrontal regions during the exposure to anxiogenic stimuli. LIMITATIONS: the small sample, the wide age range of participants and the use of psychotropic medications by most of the PDA patients.