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Background: Panic disorder is a common disabling condition with limited biomarkers. We aimed to explore the diagnostic and treatment response prediction value of functional temporal variability in people with panic disorder., Methods: Patients with panic disorder and healthy controls received resting-state functional magnetic resonance imaging scans and assessments. After 2 weeks of treatment, the patients with panic disorder were divided into remitted (RPD; n = 39) or nonremitted (NRPD; n = 43) subgroups. Baseline temporal variability was analyzed between the panic disorder and control groups as well as between RPD and NRPD subgroups., Results: Our sample included 82 patients with panic disorder (39 RPD, 43 NRPD) and 105 controls. The panic disorder group showed decreased temporal variability in the left posterior cingulate gyrus (PCG), right lingual gyrus, right fusiform gyrus, and right thalamus (all p < 0.05, Bonferroni-corrected). A combination of variability in the lingual gyrus, PCG, and thalamus had optimal predictive value for distinguishing between the panic disorder and control groups (area under the curve = 0.776, sensitivity = 0.781, specificity = 0.732). In addition, the RPD subgroup showed significantly lower temporal variability in the left insula, right PCG, and bilateral lingual gyrus than the NRPD subgroup and control group (all p < 0.05, Bonferroni-corrected). Variability in the left insula and left lingual gyrus negatively correlated with the reduction rate of panic symptoms (all p < 0.05, Bonferroni-corrected)., Limitations: Functional brain images were collected only at baseline and may have been affected by medication use. Also, the follow-up period was only 2 weeks; sustained clinical remission may require longer follow-up., Conclusion: Combining lingual gyrus, PCG, and thalamus temporal variability alterations helped distinguish patients with panic disorder from healthy controls. The temporal variability in the insula and lingual gyrus are potential biomarkers for the treatment of panic disorder., Competing Interests: Competing interests:: None declared., (© 2024 CMA Impact Inc. or its licensors.)

Abnormal functional connectivity (FC) within the fear network model (FNM) has been identified in panic disorder (PD) patients, but the specific local structural and functional properties, as well as effective connectivity (EC), remain poorly understood in PD. The purpose of this study was to investigate the structural and functional patterns of the FNM in PD. Magnetic resonance imaging data were collected from 33 PD patients and 35 healthy controls (HCs). Gray matter volume (GMV), degree centrality (DC), regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) were used to identify the structural and functional characteristics of brain regions within the FNM in PD. Subsequently, FC and EC of abnormal regions, based on local structural and functional features, and their correlation with clinical features were further examined. PD patients exhibited preserved GMV, ReHo, and ALFF in the brain regions of the FNM compared with HCs. However, increased DC in the bilateral amygdala was observed in PD patients. The amygdala and its subnuclei exhibited altered EC with rolandic operculum, insula, medial superior frontal gyrus, supramarginal gyrus, opercular part of inferior frontal gyrus, and superior temporal gyrus. Additionally, Hamilton Anxiety Scale score was positively correlated with EC from left lateral nuclei (dorsal portion) of amygdala to right rolandic operculum and left superior temporal gyrus. Our findings revealed a reorganized functional network in PD involving brain regions regulating exteroceptive-interoceptive signals, mood, and somatic symptoms. These results enhance our understanding of the neurobiological underpinnings of PD, suggesting potential biomarkers for diagnosis and targets for therapeutic intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The effects of panic disorder (PD) and pharmacotherapy on brain functional hubs in drug-free patients, and the utility of their degree centrality (DC) in diagnosing and predicting treatment response (TR) for PD, remained unclear., Aims: This study aimed to assess the effects of PD and paroxetine on brain functional hubs in drug-free patients and to identify neuroimaging biomarkers for diagnosing and predicting TR in patients with PD., Methods: Imaging data from 54 medication-free PD patients and 54 matched healthy controls (HCs) underwent DC and functional connectivity (FC) analyses before and after a 4-week paroxetine treatment. Diagnosis and prediction of TR models for PD were constructed using support vector machine (SVM) and support vector regression (SVR), with DC as features., Results: Patients with PD showed aberrant DC and FC in the anterior cingulum, temporal, and occipital areas compared with HCs at baseline. After treatment, DC of the patients increased in the calcarine cortex, lingual gyrus, and cerebellum IV/V, along with improved clinical symptoms. Utilizing voxel-wise DC values at baseline, the SVM effectively distinguished patients with PD from HCs with an accuracy of 83.33%. In SVR, the predicted TR significantly correlated with the observed TR (correlation coefficient ( r ) = 0.893, Mean Squared Error = 0.009)., Conclusion: Patients with PD exhibited abnormal DC and FC, notably in the limbic network, temporal, and occipital regions. Paroxetine ameliorated patients' symptoms while altering their brain FC. SVM and SVR models, utilizing baseline DC, effectively distinguished the patients from HCs and accurately predicted TR., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

CO 2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO 2 , and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO 2 /pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO 2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO 2 , males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO 2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO 2 exposure in mice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare and have no relevant financial or non- financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Panic disorder is a psychiatric disorder characterized by recurrent panic attacks, with a prevalence of ~ 4% in the general population, causing heavy personal and socioeconomic burdens. The similarities of animal defense responses to clinical panic attack symptoms in humans make it possible to translate neuroanatomical pathways identified in animal studies to panic disorder in humans. Therefore, in this review we first present a basic overview of panic disorder in humans including the main subtypes, models commonly used to trigger panic attacks, related hypotheses, the neurotransmitter systems that may be involved, and the current clinical treatments to give the reader a comprehensive understanding of panic disorder. The animal section introduces the models that trigger panic-like behavior in animals and the brain regions that may be involved, providing insights for future elucidation of the neural circuit mechanisms behind panic attacks., (© 2023. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Objective: The brain network in panic disorder (PD) is still an intriguing issue for research. In this study, we hoped to investigate the role of DC (degree centrality) for the pathophysiology of PD, especially for the fear network. Methods: We enrolled 60 patients with PD and 60 controls in the current study. The gender and age were matched for two groups. All participants received the resting-state functional magnetic resonance imaging to survey the baseline brain activity. Then the DC values of all participants were using REST toolbox. We also compared the DC values between PD and controls. The statistical threshold was set as FDR (false discovery rate) < 0.05. Results: The DC values were significantly lower in the right superior frontal gyrus of PD patients compared to controls (FDR < 0.05). In addition, a negative correlation between the DC values and panic severity was observed in the right superior frontal gyrus and left inferior frontal gyrus. However, there was no significant association between the DC values and illness duration. Conclusion: The DC seemed significantly altered in the frontal lobe of PD patients. The role of the frontal lobe might be more emphasized in the pathophysiology research for PD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Default mode network (DMN) is a set of functional brain structures coherently activated when individuals are in resting-state. In this study, we constructed multi-frequency band resting-state EEG-based DMN functional network models for major psychiatric disorders to easily compare their pathophysiological characteristics. Phase-locking values (PLVs) were evaluated to quantify functional connectivity; global and nodal clustering coefficients (CCs) were evaluated to quantify global and local connectivity patterns of DMN nodes, respectively. DMNs of patients with post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), panic disorder, major depressive disorder (MDD), bipolar disorder, schizophrenia (SZ), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were constructed relative to their demographically-matched healthy control groups. Overall DMN patterns were then visualized and compared with each other. In global CCs, SZ and AD showed hyper-clustering in the theta band; OCD, MCI, and AD showed hypo-clustering in the low-alpha band; OCD and MDD showed hypo-clustering and hyper-clustering in low-beta, and high-beta bands, respectively. In local CCs, disease-specific patterns were observed. In the PLVs, lowered theta-band functional connectivity between the left lingual gyrus and the left hippocampus was frequently observed. Our comprehensive comparisons suggest EEG-based DMN as a useful vehicle for understanding altered brain networks of major psychiatric disorders., (© 2021. The Author(s).)

Abstract: The objective of this study was to investigate potential correlates of dispositional optimism and quality of life in patients with depression and panic disorder. The study used a cross-sectional design. The analyzed sample consisted of 77 participants with panic disorder and 75 participants with depression attending two outpatient clinics at the Psychiatry Institute of the Federal University of Rio de Janeiro. Both groups presented similar impairments in optimism and quality of life. In the panic disorder group, optimism scores were significantly correlated with a decrease in anxiety and depression scores (r = 0.26 and r = 0.37, respectively); in the depression group, increases in optimism scores were significantly correlated with decreases in anxiety and depression scores (r = 0.23 and r = 0.3, respectively). The present study showed that high anxiety and depression are correlated with poor optimism and quality of life scores in panic disorder and depression groups. Thus, psychological treatments that can address these topics, besides acute symptoms, are crucial to the absolute recovery of patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Panic disorder (PD) is a harmful mental condition that causes relapsed and persistent impairment. In the treatment of PD, the prognosis for PD should be considered. However, the relationship between pharmacotherapy and biomarkers, for predicting a better response through neuroimaging, is a little known. The purpose of the present study was to examine whether there would be the initial white matter (WM) regions associated with the remission in 6 months. A total of 104 patients with PD were investigated in the study. After six months, there were 17 remission patients with PD and 81 non-remission patients. The Panic Disorder Severity Scale, Albany Panic and Phobia Questionnaire, Anxiety Sensitivity Inventory-Revised, Beck Anxiety Inventory, and Beck Depression Inventory were assessed for all patients at baseline. We compared the diffusion indices between remission and non-remission group at 6 months using Tract-Based Spatial Statistics. The results showed that the fractional anisotropy (FA) values were significantly higher in the non-remitter group compared with those in the remitter group in the WM regions, such as the posterior corona radiata and superior longitudinal fasciculus, at the 6 month evaluation. The logistic regression analysis with clinical symptom severity and FA values of the WM regions as covariates showed that FA values in those regions and the Beck Depression Inventory-II predicted poor remission. This study suggests that posterior corona radiata and superior longitudinal fasciculus are related to potential predictive factors of 6-month remission in patients with PD. WM regions associated with the long-term remission should be verified with further investigations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of suffocation, and paresthesias. Doxapram is an analeptic capable of inducing panic attacks with respiratory symptoms in individuals diagnosed with the disorder; however, its neuroanatomical targets and its effects on experimental animals remain uncharacterized. One of the brain regions proposed to trigger panic attacks is the midbrain periaqueductal gray (PAG). Therefore, in this study, we evaluated the effects of doxapram in Fos (c-Fos) protein expression in the PAG and characterized its cardiorespiratory and behavioral effects on the elevated T maze and in the conditioned place aversion (CPA) paradigms. Doxapram increased Fos expression in different columns of the PAG, increased respiratory frequency, decreased heart rate, and increased arterial pressure when injected via intravenous route. Alprazolam, a panicolytic benzodiazepine, injected via intraperitoneal route, decreased respiratory frequency, whereas URB597, an anandamide hydrolysis inhibitor injected via intraperitoneal route, was ineffective. Doxapram injected via intraperitoneal route induced an anxiogenic-like effect in the elevated T-maze model; however, it failed to induce CPA. This study suggests that the cardiorespiratory and behavioral effects of doxapram in rodents serve as an experimental model that can provide insights into the neurobiology of panic attacks., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The wearing of respiratory protective devices (RPDs) correctly and continually in situations where people are at risk of respiratory infections is crucial for infection prevention. Certain people are poorly compliant with RPDs due to RPD-related annoyance, including respiratory discomfort. We hypothesized that individuals vulnerable to panic attacks are included in this group. No published studies on this topic are available. The evidence for our hypothesis was reviewed in this study as a starting point for future research., Methods: We selected a set of experimental studies that measured the respiratory physiological burden in RPD wearers through objective and validated methods. We conducted a bibliographic search of publications in the PubMed database (January 2000-May 2020) to identify representative studies that may be of interest for panic respiratory pathophysiology., Results: Five studies were included. Wearing RPDs exerted significant respiratory effects, including increased breathing resistance, CO 2 rebreathing due to CO 2 accumulation in the RPD cavity, and decreased inhaled O 2 concentration. We discussed the implications of these effects on the respiratory pathophysiology of panic., Limitations: Most studies had a small sample size, with a preponderance of young participants. Different methodologies were used across the studies. Furthermore, differences in physical responses between wearing RPDs in experimental settings or daily life cannot be excluded., Conclusions: This research supports the idea that panic-prone individuals may be at higher risk of respiratory discomfort when wearing RPDs, thereby reducing their tolerance for these devices. Strategies to decrease discomfort should be identified to overcome the risk of poor compliance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Anxiety is commonly observed together with skin diseases and can aggravate them, while skin diseases can increase anxiety. The relationship of skin diseases observed in panic disorder with quantitative electroencephalography (QEEG) findings has not been investigated yet. The aim of this study is to compare the absolute alpha and delta power of panic disorder patients with and without skin disease., Methods: 246 panic disorder patients, 19 of whom had skin disease and 227 of whom did not have skin disease, were included in the study. Panic disorder severity scale (PDSS) scores of patients were recorded, and QEEG recording was performed. Absolute alpha and delta power and PDSS scores were compared between the two groups., Results: It was found that the absolute delta power in the left hemisphere was lower and PDSS scores were higher in the patients with skin diseases compared to the control group. In the patients with skin disease, decreased delta power in the left hemisphere may cause impairment in the processing of positive emotions and may cause trait anxiety., Conclusion: Trait anxiety may increase susceptibility to skin diseases by disrupting cutaneous homeostasis resulting from the prolonged sympathetic nervous system activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Panic disorder (PD) has been linked to abnormalities in information processing. However, only little evidence has been published for sensory gating in PD. Sensory gating describes the brain's ability to exclude stimuli of low relevance from higher level information processing, thereby sustaining efficient cognitive processing. Deficits in sensory gating have been associated with various psychiatric conditions, most prominently schizophrenia. In this case-control event-related potential study, we tested 32 patients with PD and 39 healthy controls in a double click paradigm. Both groups were compared with regard to pre-attentive (P50), early-attentive (N100), and late-attentive (P200) sensory gating indices. Contrary to a hypothesized deficit, PD patients and healthy controls showed no differences in P50, N100 and P200 values. These results suggest that sensory gating seems to be functional across the pre-attentive, early-attentive, and late-attentive time span in this clinical population. Given this consistency across auditory sensory gating indices, further research aiming to clarify information processing deficits in PD should focus on other neurophysiological markers to investigate information processing deficits in PD (eg, P300, error-related negativity or mismatch negativity).

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Fear conditioning and extinction serve as a dominant model for the development and maintenance of pathological anxiety, particularly for phasic fear to specific stimuli or situations. The validity of this model would be supported by differences in the physiological or subjective fear response between patients with fear-related disorders and healthy controls, whereas the model's validity would be questioned by a lack of such differences. We derived pupillometry, skin conductance response and startle electromyography as well as unconditioned stimulus expectancy in a two-day fear acquisition, immediate extinction and recall task and compared an unmedicated group of patients (n = 73) with phobias or panic disorder and a group of patients with posttraumatic stress disorder (PTSD, n = 21) to a group of carefully screened healthy controls (n = 35). Bayesian statistics showed no convincing evidence for a difference in physiological and subjective responses between the groups during fear acquisition, extinction learning or recall. Only the PTSD subgroup had altered startle reactions during extinction learning. Our data do not provide evidence for general differences in associative fear or extinction learning in fear-related pathologies and thereby question the diagnostic validity of the associative fear learning model of these disorders., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Drugs targeting N-methyl-d-aspartate (NMDA) receptors and the ability to learn new associations have been proposed as adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. Panic disorder patients were randomised to single-dose d-cycloserine (250 mg; N = 17) or matching placebo (N = 16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces (primary outcome) and amygdala response to threat (secondary outcome). Clinical symptom severity was measured the day before and after treatment, and at 1- and 6-months follow-up (secondary outcome). d-cycloserine was associated with greater clinical recovery at 1-month follow-up than placebo (d-cyloserine 71% vs placebo 25%), with the placebo group matching the clinical gains of the d-cycloserine group during 6-months follow-up (d-cycloserine 71% vs placebo 44%). One day after treatment, threat bias for fearful faces and amygdala threat response was lower in the drug compared to placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. While this experimental study is of a preliminary nature due to the limited sample size, these findings highlight a neurocognitive potential mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate development of combination treatments for anxiety. (d-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107)., Competing Interests: Declaration of competing interest AR and AN report no conflicts of interest. MB has received travel expenses from Lundbeck for attending conferences, and has acted as a consultant for J&J and CHDR. CH has received consultancy fees from Lundbeck, P1vital, J&J, Pfizer and Servier., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Heart rate variability (HRV) and end tidal CO2 (ETCO2) in relation to treatment response have not been studied in Latino populations or in comorbid asthma and panic disorder (PD). An extension of previously published research, the current study explored psychophysiological variables as possible mediators of treatment response. Latino treatment completers (N = 32) in the Bronx with asthma-PD received either Cognitive-Behavioral Psychophysiological Therapy (CBPT) or Music Relaxation Therapy (MRT). CBPT included HRV-biofeedback (HRVB); in-the-moment heart rate data to help an individual learn to influence his/her own heart rate. The sample was primarily female (93.8%) and Puerto Rican (81.25%). Treatment groups did not differ on demographics, except for less education in CBPT. The Panic Disorder Severity Scale (PDSS) and Asthma Control Questionnaire (ACQ) assessed changes in symptoms. HRV and ETCO2 were measured at four of eight therapy sessions. Baseline ETCO2 and changes in HRV from first to last of psychophysiology sessions were investigated as mediators of change on ACQ and PDSS. Mixed model analyses indicated in the CPBT group, changes in both asthma control and PD severity were not mediated by changes in HRV. In the CBPT and MRT groups combined, changes in PD severity were not mediated by baseline ETCO2. These findings may be due to the brevity of HRVB in CBPT, multiple treatment components, ETCO2 not directly targeted, and/or unique physiological pathways in Latinos with asthma-PD.

Although the "panic" word has been abundantly linked to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic in the press, in the scientific literature very few studies have considered whether the current epidemic could predispose to the onset or the aggravation of panic attacks or panic disorder. Indeed, most studies thus far have focused on the risk of increase and aggravation of other psychiatric disorders as a consequence of the SARS-CoV-2 epidemic, such as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). Yet, risk of onset or aggravation of panic disorder, especially the subtype with prominent respiratory symptoms, which is characterized by a fear response conditioning to interoceptive sensations (e.g., respiratory), and hypervigilance to these interoceptive signals, could be expected in the current situation. Indeed, respiratory symptoms, such as coughs and dyspnea, are among the most commonly associated with the SARS-CoV-2 (59-82% and 31-55%, respectively), and respiratory symptoms are associated with a poor illness prognosis. Hence given that some etiological and maintenance factors associated with panic disorder - i.e., fear conditioning to abnormal breathing patterns attributable or not to the COVID-19 (coronavirus disease 2019), as well as hypervigilance towards breathing abnormalities - are supposedly more prevalent, one could expect an increased risk of panic disorder onset or aggravation following the COVID-19 epidemic in people who were affected by the virus, but also those who were not. In people with the comorbidity (i.e., panic disorder or panic attacks and the COVID-19), it is particularly important to be aware of the risk of hypokalemia in specific at-risk situations or prescriptions. For instance, in the case of salbutamol prescription, which might be overly used in patients with anxiety disorders and COVID-19, or in patients presenting with diarrhea and vomiting. Hypokalemia is associated with an increased risk of torsade de pointe, thus caution is required when prescribing specific psychotropic drugs, such as the antidepressants citalopram and escitalopram, which are first-line treatments for panic disorder, but also hydroxyzine, aiming at anxiety reduction. The results reviewed here highlight the importance of considering and further investigating the impact of the current pandemic on the diagnosis and treatment of panic disorder (alone or comorbid with the COVID-19)., (Copyright © 2020 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Panic disorder (PD), defined by repeated and unexpected panic attacks, severely affects patients' living quality and social function. Perimenopausal women are high-risk group of PD and suffer greatly from it. Modern medicine therapies for this disorder have many side reactions and poor effects, so nonpharmacological modality is an urgent need. Although acupoint catgut embedding is widely used in clinical practice, there is no persuasive evidence of its effect for perimenopausal PD. The aim of this study is to investigate the effectiveness and safety of acupoint catgut embedding for perimenopausal PD and to elucidate the correlations among brain neural activation, bio-markers (amino acids) and clinical outcomes with radiographic evidence, thus to explore its neural mechanism., Methods: The parallel designed, exploratory randomized controlled trial will include 70 outpatients with perimenopausal PD recruited from two hospitals of Chinese Medicine. These subjects will be randomly allocated to an intervention group (Group Embedding) and a control group (Group Medication) in a 1:1 ratio. The subjects in the intervention group will receive acupoint catgut embedding treatment two weeks a time in the following predefined acupuncture points: Shenshu (BL23), Sanyinjiao (SP6), Guanyuan (RN4), Ganshu (BL18), Zusanli (ST36) and Pishu (BL20). The included women of the control group will take 0.4 mg Alprazolam tablet orally, 1 tablet a time, 3 times a day. There is a study period of 3 months and a follow-up period of 1 month for each group. The primary outcomes will be the following therapeutic indexes: the frequency of panic attack, Panic Disorder Severity Score (PDSS), and Panic-associated Symptoms Score (PASS) during the observation period and follow-up period. The changes in Hamilton Anxiety Scale (HAMA) Score and Symptom Checklist 90 (SCL-90) Score will also be compared between these two groups. Additionally, functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) scans will be done before and after the observation period to show cranial neuroimaging changes., Discussion: We present a study design and rationale to explore the effectiveness and neural mechanism of acupoint catgut embedding for perimenopausal PD. There are still several factors restrict our research such as no unified standard of diagnostic criteria and curative effect evaluation., Trial Registration: Chinese Clinical Trial Registry, ChiCTR-INR-16009724, registered in November 2016.

Background and Objectives: The autonomic nervous system (ANS) is involved in panic disorders. ANS dysfunction has been shown to be associated with ventricular arrhythmia and increased heterogeneity of ventricular repolarization. However, there remains limited evidence of the relationship between panic disorders and ventricular depolarization markers, including the Tp-e interval and Tp-e/QT ratio. This study aimed to evaluate ventricular repolarization parameters in patients with panic disorder. M aterials and M ethods: In total, 40 patients with panic disorder, diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, were included in the study group. The control group comprised of 50 age- and sex-matched healthy individuals. A standard 12 lead electrocardiogram was recorded on all participants, and heart rate, QT interval, QRS duration, Tp-e interval, and Tp-e/QT ratio were measured. Results: QRS durations and QT intervals were similar in the study and control groups. Compared to the control group, QTd, Tp-e, and cTp-e intervals as well as Tp-e/QT and Tp-e/QTc ratios were significantly increased in patients with panic disorder (p < 0.05 for all). In the study group, the Severity Measure for Panic Disorder-Adult score had a significant positive correlation with the Tp-e interval ( r = 0.369, p < 0001), cTp-e interval ( r = 0.531, p < 0.001), Tp-e/QT ratio ( r = 0.358, p = 0.001), and Tp-e/QTc ratio ( r = 0.351, p = 0.001). Conclusion: These findings indicate that panic disorders are associated with increased ventricular repolarization heterogeneity, which may be attributed to ANS dysregulation.

Despite the scientific consensus on the efficacy of psychotherapy for the treatment of psychological disorders, the evidence of treatment-related changes towards normalization of abnormal brain functions in patients is mixed. In the present experiment, we investigated whether treatment can affect early information processing, by testing abnormal event-related potentials (ERPs) evoked by internal and external signals in panic disorder. Sixteen patients with panic disorder and comorbid personality disorder and sixteen control participants performed a response-choice task and a passive viewing task in two testing sessions, separated by around 14 months. During this period, patients received psychological treatment. In agreement with previous studies of performance monitoring, the abnormal amplitude of the Ne/ERN-an index of error processing based on internal signals-did not change between the first and second testing session. However, treatment-related changes were evident for the abnormal vertex positive potential (VPP) evoked by external signals in the response-choice task and the passive viewing task. In patients, the VPP was smaller in the second session compared to the first session, whereas no significant changes occurred in controls. This result supplies evidence of treatment-related changes towards normalization in the early information processing of external visual stimuli in panic disorder., Competing Interests: The authors declare no competing interests.

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

ABSTRACT Objective: To examine whether working alliance quality and use of techniques predict improvement in Panic-Specific Reflection Function (PSRF), and misinterpretation of bodily sensations in treatments for panic disorder. Method: A sample of 161 patients received either CBT or PFPP (Panic-focused Psychodynamic therapy) within a larger RCT. Data were collected on patient-reported working alliance, misinterpretations, PSRF, observer-coded use of techniques, and interviewer-rated panic severity. Random-Intercept Cross-Lagged Panel Models assessed bi-directional associations, disentangling within- and between-patient effects, and accounting for prior change. Results: Higher alliance predicted subsequent within-patient improvement in PSRF in PFPP, but worsening in CBT. In both treatments, focus on interpersonal relationships predicted PRSF improvement (with stronger effects in CBT), while focus on thoughts and behaviors predicted worsening in PSRF. In CBT only, early focus on affect and moment-to-moment experience predicted reduced misinterpretation, while high focus on thoughts and cognitions predicted subsequent increase in misinterpretation. Conclusion: The quality of the alliance has differential effects on PSRF in distinct treatments. Interpersonal, rather than cognitive or behavioral focus, even when delivered differently within distinct treatments with high adherence, could facilitate improvement in PSRF. Additionally, early focus on affect and moment-to-moment experiences in CBT could reduce misinterpretations.

Background: Research on the link between respiratory sinus arrhythmia (RSA) and posttraumatic stress disorder (PTSD) has largely focused on average levels of RSA. However, given that rapid shifts in parasympathetic tone are necessary to maintain adaptive cardiac variability, the exclusive focus on these tonic estimates provides an incomplete quantification of parasympathetic cardiac regulation., Method: The present study is a secondary analysis of previously published data. This analysis aimed to address this limitation by examining the dynamic regulatory effect of the parasympathetic nervous system on heart rate. As such, we examined epoch-to-epoch parasympathetic cardiac regulation - operationalized as the lagged relationship between RSA and heart rate (HR) across consecutive 30-s epochs - across a single night in participants with PTSD, panic disorder (PD), comorbid PTSD and PD (PTSD + PD), and healthy controls. Electrocardiogram and respiratory signals were continuously recorded from 23 participants with PTSD, 14 with PD, 16 with PTSD + PD, and 16 control participants over a single night of sleep in a laboratory setting., Results: No group differences in tonic RSA were observed; however, participants with PTSD only and PTSD + PD exhibited significantly greater epoch-to-epoch parasympathetic cardiac regulation over the night than those with PD only and control participants. Moreover, greater severity of hyperarousal symptoms was significantly associated with increased epoch-to-epoch parasympathetic cardiac regulation among participants with PTSD only and PTSD + PD., Discussion: These data provide preliminary evidence for an upregulatory parasympathetic response to self-reported hyperarousal in participants with PTSD only and PTSD + PD reflected by increased epoch-to-epoch parasympathetic cardiac regulation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: One of the METHODS used to assess autonomic nervous system dysfunction in the etiology of panic disorder (PD) is heart rate variability (HRV). HRV is controlled by the sympathetic and parasympathetic (vagal) branches of the autonomic nervous system and reflects the capacity of autonomic stimulation by the parasympathetic system. The aim of this study was to evaluate heart rate variability (HRV) time domain parameters based on twenty four hour holter ECG analysis among drug-naive patients with panic disorder (PD) without any other medical and psychiatric comorbidity., Method: The study group consisted of 41 patients with PD and 46 healthy controls. Participants were evaluated with SCID-1 for psychiatric diagnoses. Then Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Panic Disorder Severity Scale (PDSS) and Clinical Global Impression Scale (CGI-S) were applied to participants. Twenty four hour Holter ECG outcomes were analyzed on a computer program and time domain parameters were evaluated., Results: Among the parameters analyzed from HRV, SDANN was significantly higher (p <0.001); duration of RMSSD, NN50 and pNN50 were lower in PD group than the control group (p = 0.003, p = 0.005, p = 0.047, respectively). In the correlation analysis, there was a moderate negative correlation between CGI-S and NN50 and pNN50. In logistic regression analysis, the increase in SDNN was found to increase the probability of PD by 1.11 (95% CI, 1.010-1.209); the increase in SDANN was found to decrease the probability of PD by 0.892 (95% CI, 0.818-0.973), and the increase in pNN50 was found to decrease the probability of PD by 0.523 (95% CI, 0.342-0.801)., Conclusion: The data obtained in our study confirm that there is a decrease in some HRV parameters like RMSSD, NN50 and pNN50 reflecting parasympathetic activity among patients with PD.

The gene coding for glycine receptor β 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 «risk») 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Anxiety is characterized by altered responses under uncertain conditions, but the precise mechanism by which uncertainty changes the behaviour of anxious individuals is unclear. Here we probe the computational basis of learning under uncertainty in healthy individuals and individuals suffering from a mix of mood and anxiety disorders. Participants were asked to choose between four competing slot machines with fluctuating reward and punishment outcomes during safety and stress. We predicted that anxious individuals under stress would learn faster about punishments and exhibit choices that were more affected by those punishments, thus formalizing our predictions as parameters in reinforcement learning accounts of behaviour. Overall, the data suggest that anxious individuals are quicker to update their behaviour in response to negative outcomes (increased punishment learning rates). When treating anxiety, it may therefore be more fruitful to encourage anxious individuals to integrate information over longer horizons when bad things happen, rather than try to blunt their responses to negative outcomes.

Patients with panic disorder show abnormalities in threat processing and regulation, both on a behavioural and neural level. Better understanding of the underlying mechanisms could help to develop new treatment strategies. In this study, we investigated brain region activation in 18 patients with untreated panic disorder (PD) and 17 healthy controls (HC) during the processing of emotional faces with fearful, happy and neutral expressions, using functional MRI. The intensity of the expressions was either prototypically high, medium or low. PD patients showed significantly increased activity in the dorso-medial prefrontal cortex (dmPFC) in response to faces in general and specifically for happy faces. While HC showed a decreased amygdala response to medium/low fearful versus high fearful faces, this effect was not present in PD: amygdala activation was stable across all fearful faces in this group. Psycho-physiological interaction analyses indicated more negative connectivity between the amygdala and prefrontal areas in the PD group during the task. Amygdala activation in panic patients appears to be less sensitive to decreasing intensities of fearful facial expressions and salience monitoring areas were less active during fearful faces in general in this group. This suggests PD patients might avoid more extensive processing of fearful faces., (Copyright © 2019. Published by Elsevier B.V.)

Heightened responsivity to unpredictable, and perhaps predictable, threat characterizes some internalizing disorders and may be vulnerability factors for psychopathology as well. However, few studies have directly tested whether individual differences in unpredictable and/or predictable threat responding longitudinally predict symptoms of psychopathology and functional outcomes. Examining functioning is particularly important given that functioning is separable from symptoms of psychopathology. The present study examined whether electromyography startle measures of predictable and/or unpredictable threat responding was associated with interviewer-assessed symptoms of internalizing psychopathology and functional impairment at baseline (n = 409) and one-year follow-up (n = 104). Elevated startle responding to unpredictable and predictable threat longitudinally predicted a worsening of functioning over time and this effect was independent of change of symptoms over time. Importantly, threat responding at baseline predicted functional impairment during the follow-up independent of the effects of DSM-defined fear-based (e.g., panic disorder) or distress-misery (e.g., major depressive disorder) internalizing disorders. These findings provide initial support for the incremental validity of neurobiological vulnerability markers of threat responding over and above DSM disorders and highlight the importance of distinguishing functional outcomes from symptom outcomes., (Published by Elsevier B.V.)

Objective: Panic disorder (PD) is now recognized as a common and important problem in children, and particularly adolescents, and one that can negatively affect daily well-being and educational performance. The aim of this study was to investigate the relationship between heart rate variability (HRV) and the severity of symptoms before and after treatment with psychotherapy and fluoxetine., Methods: The PD study group consisted of 23 children diagnosed with PD and the healthy control (HC) group comprised 27 healthy children. Panic-anxiety symptoms were measured using 2 assessments performed before and after treatment. HRV was evaluated with a 24-hour Holter examination., Results: According to the analysis of the 24-hour, all-day Holter device recordings, the high frequency (HF) and parasympathetic (%) scores in the PD group were lower than those of the HC group (p<0.05). The low frequency (LF)/HF ratio and sympathetic (%) scores in the PD group were higher than those of the HC group (p<0.05). The analysis of daytime readings indicated that the HF values of the PD group were lower than those of the HC group (p<0.05), while the very LF/HF ratio and LF/HF ratio were higher than those of the HC group (p<0.05). Analysis of nighttime Holter results revealed that the rMSSD, pNN50, and HF readings of the PD group were lower than those of the HC group (p<0.05), while the LF/HF ratio in PD patients was higher than that seen in the HC group (p<0.05)., Conclusion: In children and adolescents with PD, increased sympathetic activity can cause changes in some HRV parameters. Some of these changes may return to normal with treatment.

Given the particular relevance of arousal and alerting in panic disorder (PD), here the alerting network was investigated (1) contrasting patients with PD and healthy controls, (2) as a function of anxiety sensitivity constituting a dimensional measure of panic-related anxiety, and (3) as a possible correlate of treatment response. Using functional magnetic resonance imaging (fMRI), 45 out-patients with PD (f = 34) and 51 matched healthy controls were investigated for brain activation patterns and effective connectivity (Dynamic Causal Modeling, DCM) while performing the Attention Network Task (ANT). Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). Forty patients and 48 controls were re-scanned after a 6 weeks cognitive-behavioral treatment (CBT) or an equivalent waiting time, respectively. In the alerting condition, patients showed decreased activation in fronto-parietal pathways including the middle frontal gyrus and the superior parietal lobule (MFG, SPL). In addition, ASI scores were negatively correlated with connectivity emerging from the SPL, the SFB and the LC and going to the MFG in patients but not in healthy controls. CBT resulted in an increase in middle frontal and parietal activation along with increased connectivity going from the MFG to the SPL. This change in connectivity was positively correlated with reduction in ASI scores. There were no changes in controls. The present findings point to a pathological disintegration of the MFG in a fronto-parietal pathway in the alerting network in PD which was observed to be reversible by a successful CBT intervention.

The present article aims to illustrate and review evidence on how associative learning involving interoceptive stimuli (interoceptive conditioning) can lead to changes in physiological, emotional, and perceptual outcomes. We first outline a functional perspective on Pavlovian conditioning and provide a general introduction and historical background on interoceptive conditioning as a special instance of Pavlovian conditioning. Next, biological and learning accounts of panic disorder are discussed, followed by an analysis of which stimuli and responses may be most promising to model learning that is relevant to panic disorder. Finally, studies on interoceptive fear conditioning with respiratory stimuli are reviewed and discussed, and future directions are outlined., (© 2019 Society for Psychophysiological Research.)

Patients with panic disorder (PD) exhibit abnormalities in early-stage information processing, even for the nonthreatening stimuli. A previous event-related potential study reported that PD patients show a deficit in sensory gating (SG), a protective mechanism of the brain to filter out irrelevant sensory inputs. However, there is no clear understanding about the neural correlates of SG deficits in PD. Moreover, whether SG deficits, if any, are associated with clinical manifestations remain unknown. In this study, 18 patients with PD and 20 age- and gender-matched healthy controls were recruited to perform auditory paired-stimulus paradigm using magnetoencephalographic (MEG) recordings. Results showed that PD patients demonstrated significantly higher M50 SG ratios in the right inferior frontal gyrus (RIFG) and higher M100 SG ratios in both RIFG and right superior temporal gyrus (RSTG) than those of the control group. It was important to note that in the RIFG, the M50 SG ratios correlated significantly with the scores of Body Sensation Questionnaire (BSQ) and Distractibility scale of Sensory Gating Inventory among patients with PD. In conclusion, this study suggests that PD patients exhibited a deficient ability to filter out irrelevant information, and such a defect might lead to cognitive misinterpretation of somatic sensations and distractibility., (Copyright © 2019. Published by Elsevier B.V.)

Abnormalities in the kynurenine pathway (KP) have been implicated in the cognitive deficits of psychiatry disorders, possibly through cytokines that increase the activity of indoleamine-2,3 dioxygenase (IDO), a key enzyme for tryptophan-to-kynurenine conversion. Some studies on panic disorder (PD) have detected elevated cytokines in blood. We aimed to determine the extent to which elevated peripheral cytokine levels and kynurenine/tryptophan (kyn/tryp) ratio (1) are biological markers for PD patients and (2) are related to cognition in PD. Seventy-eight PD patients and matched healthy controls were assessed for peripheral serum levels of interleukin (IL)-2R, IL-1β, IL-10, kynurenine and tryptophan. The subjects were evaluated for episodic and short-term memory, selective attention and cognitive flexibility. In patients, IL-2R levels, which are involved in the regulation of IDO, were significantly associated with levels of kynurenine (p = .029), but this association was not observed in controls. Importantly, an elevated kyn/tryp ratio significantly predicted poor digit span forward (p = .004) and total (p = .004) scores in individuals with PD. This study is the first to link blood biomarkers of infiammation and the KP with cognitive deficits in PD subjects, suggesting that those with an elevated kyn/tryp ratio might have short-term auditory memory impairment. These findings indicate that treatments targeting the KP may ameliorate cognitive abnormalities in PD patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.

Illness anxiety disorder is a primary disorder of anxiety about having or developing a serious illness. The core feature is the cycle of worry and reassurance seeking regarding health, as opposed to a focus on relief of distress caused by somatic symptoms (as in Somatic Symptom Disorder). Clinically significant health anxiety is common, with estimates ranging up to 13% in the general adult population. There are evidence-based treatments, including psychopharmacology and cognitive behavioral therapy, that can significantly alleviate symptoms. An understanding of the core psychopathology and clinical features of illness anxiety disorder is essential to fostering a working alliance with patients with health anxiety, as is the maintenance of an empathic, curious, and nonjudgmental stance toward their anxiety. Collaboration between medical providers is essential to avoid the pitfalls of excess testing and medical treatment.

Objective: The objective of this study is to perform a systematic review and meta-analysis on whether patients with panic disorder (PD) and their healthy first-degree relatives have an increased sensitivity to carbon dioxide inhalation test compared to healthy controls (HC) or patients with psychiatric disorders other than panic disorder., Method: The databases of PubMed, EMBASE and PsycNET were searched using Boolean operators "panic AND carbon dioxide" and "panic AND CO2". Selected research articles were classified according to the carbon dioxide concentrations used in testing and the clinical characteristics of the samples. The assumption of heterogeneity across the studies was assessed by chi square based Q and I2 statistics. Publication biases were explored by Begg-Mazumdar's and Egger's tests in addition to funnel graphics. Odds ratios representing effect size of the carbon dioxide inhalation procedure were calculated according to fixed effect and random effect models after obtaining percent weight effects of each study., Results: Meta-Analysis was conducted on 33 research studies that include 2114 participants totally. Participants with PD experienced significantly more frequent panic attacks (PA) compared to HC following in both 5% (OR=14.713, 95% CI 7.532 - 28.739) and 35% carbon dioxide inhalation (OR=11.507, 95% CI 7.775 - 17.031). HC who have a first-degree relative with PD experienced PA approximately 3 times more than HC who have not a first-degree relative with PD (OR=2.658, 95% CI 1.678 - 4.212) following carbon dioxide inhalation test. Participants with PD experienced significantly more frequent PA than the patients with other psychiatric disorders following the carbon dioxide inhalation test (OR = 3.524, 95% CI 1.945 - 6.384)., Conclusion: There is an increased sensitivity of carbon dioxide inhalation in patients with PD and their healthy first-degree relatives. The role and possible mechanisms of carbon dioxide in etiology and physiopathology of PD should be studied extensively.

Purpose: To evaluate the function of the utriculus and sacculus and their central connections by ocular and cervical vestibular-evoked myogenic potentials (oVEMPs and cVEMPs), and the function of high-frequency VOR of the semicircular canals by video head impulse test (vHIT) in patients with panic disorder (PD)., Methods: Forty-eight patients with PD (21 with agoraphobia) and 20 sex- and age-matched healthy controls took part in the investigation. The vestibulo-ocular reflex (VOR) gains and latencies and peak-to-peak amplitudes of sound-induced VEMPs were measured and compared with those of healthy controls., Results: Any statistical differences in the parameters of cVEMP and oVEMP responses between both PD patients groups and between patients and healthy controls were not observed. Also, significant differences between VOR in patients and healthy controls were not found. The VOR gain, bilaterally in the three semicircular canals was within normal limits (0.8-1.2) for 67%, and higher for 33% of the patients with PD. Overt and covert saccades were not observed. The relationship between higher VOR gains and the increase of postural instability when a sensory conflict exists (standing on foam pad with eyes closed) for patients with PD was established., Conclusion: The VEMPs and vHIT tests demonstrated that there is no evidence of hypofunction of the semicircular canals in the high-frequency spectrum of VOR functioning. Nor are there any indications of impairment of the otolith system in patients with PD, regardless of their subjective vestibular sensations. The findings of the current study confirm the proposed link between anxiety, panic symptoms and postural instability in PD patients.

Background: Hypervigilance to panic-related stimuli is believed to play a critical role in the pathogenesis of panic disorder. The current event-related potential study explored whether this hyperresponsivity occurred in the absence of focused attention., Methods: Mismatch negativity (MMN) responses to panic-related vs. neutral deviants were assessed in 15 medication-free panic patients without agoraphobia and 16 healthy controls using a reverse-standard-deviant paradigm., Results: Panic patients relative to healthy controls exhibited an enhanced MMN in response to panic-related sounds but a reduced MMN in response to neutral sounds. Furthermore, MMN responses were delayed in panic patients compared to healthy controls, irrespective of stimulus type., Limitation: The sample size is relatively small., Conclusions: Our data provide evidence that panic disorder was associated with an increased sensitivity to panic-related changes, accompanied by a reduced sensitivity to other acoustic changes as well as a general slow-down of cognitive processing during the preattentive processing stage., (Copyright © 2019. Published by Elsevier B.V.)

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB 1 and CB 2 antagonists (AM251 and AM630, respectively), and mimicked by CB 1 and CB 2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB 1 and CB 2 receptors in this brain region., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Heart Rate Variability (HRV) parameters have been used to evaluate the autonomic nervous system. We hypothesized that patients with major depressive disorder (MDD) and panic disorder (PD) showed different HRV profiles compared to healthy controls. We also hypothesized that we could predict the responder groups in the MDD and PD patients, using differences in HRV indices between the stress and rest phases., Methods: 28 MDD patients and 29 PD patients were followed for 12 weeks, and we also followed 39 healthy control subjects. We measured HRV parameters at the rest, stress, and recovery phases., Results: Patients with MDD and PD demonstrated lower pNN50 than controls during the stress (F = 7.49, p = 0.001), and recovery phases (F = 9.43, p = 0.0001). Patients with MDD and PD also showed higher LF/HF ratio than controls during the stress phase (F = 6.15, p = 0.002). Responders in the PD group presented a lower level of LF/HF ratio during the stress phase compared to non-responders (F = 10.14, p = 0.002), while responders in the MDD group showed a lower level of heart rate during all three phases, compared to non-responders. Additionally, we could predict treatment response in patients with MDD using ΔLF/HF ratio (OR: 1.33, 95% CI = 1.07-1.65, p = 0.011) and ΔpNN50 (OR: 1.49, 95% CI 1.09-1.77, p = 0.014)., Conclusion: The changes of HRV parameters of pNN50 and LF/HF ratio between the stress and recovery phase may be clinical markers of predictors of treatment responsiveness in MDD and PD patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose/background: The purpose of this study was to examine the relationships between ytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms, brain-derived neurotrophic factor (BDNF) plasma levels, and treatment responses to escitalopram in Chinese patients with panic disorder (PD)., Methods/procedures: Ninety patients with PD were administered the Panic Disorder Severity Scale-Chinese Version (PDSS-CV) and Hamilton Anxiety Scale (HAMA-14) from baseline to 8 weeks. Escitalopram treatment (10 mg/d) was administered for 8 consecutive weeks. Three CYP2C19 metabolizers, including extensive metabolizers, intermediate metabolizers, and poor metabolizers (PMs), and 5 CYP2C19 genotypes were detected by polymerase chain reaction-genotyping microarray analysis. Baseline plasma BDNF levels were tested using human BDNF enzyme-linked immunosorbent assay kits., Findings/results: Our findings showed no significant differences in demographic data, baseline PDSS-CV scores, or HAMA-14 scores between the 3 CYP2C19 metabolizer groups (P's > 0.05). Repeated-measures analysis showed a significant reduction in PDSS-CV (F = 221.49, df = 3, P < 0.001) and HAMA-14 (F = 260.47, df = 3, P < 0.001) scores over 8 weeks in PD patients. In addition, patients with PMs had a greater reduction in HAMA-14 scores (F = 2.14, P = 0.049) than did those with extensive metabolizers and intermediate metabolizers. Moreover, our findings showed that patients with *2/*2 genotypes had a greater reduction in PDSS-CV scores than did those with other genotypes (F = 2.14, df = 12, P = 0.015)., Implications/conclusions: Our study provides preliminary evidence of the effects of CYP2C19 PMs on treatment responses to escitalopram in Chinese PD patients, but no significant correlation between treatment responses and BDNF levels was found.

Patients with progressive cognitive decline mostly suffer from degenerative disease and carry a relatively poor prognosis. But small groups among these patients have a potentially treatable cause of illness and therefore every patient with dementia needs to be considered treatable unless proved otherwise. This group can be identified only by high degree of suspicion based on clinical clues. We have evaluated the validity of some simple clinical clues which we noticed in our patients with immune mediated dementias. The Panic score, Epsworth sleepiness score, catatonic symptoms and history of seizures were compared between 23 and 11 patients with serologically confirmed anti-NMDA antibody and anti-VGKC antibody associated encephalitis respectively. They were compared with 20 patients with probable behavioral variant of Frontotemporal dementia (bvFTD) and 20 patients with probable Alzheimer's disease (AD). Chi-square test was used to compare across the groups and there was significant difference (P < 0.05) across the 4 groups comprising anti NMDA encephalitis, anti VGKC encephalitis, FTD and AD among the four variables (Panic scores, Catatonic symptoms, Epsworth sleepiness score and seizures) studied. Our study revealed that panic and sleepiness is highly significant when tested across all groups and catatonia showed a trend towards NMDA and when compared with degenerative dementia versus immune mediated syndromes all the 4 parameters were highly significant This simple bedside TRIAD of panic, sleepiness with either of catatonia or seizures if found in patients it is appropriate to order antibody assessment before anything else is planned. This needs to be evaluated in a larger sample., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite considerable effort, the neural correlates of altered threat-related processing in panic disorder (PD) remain inconclusive. Mental imagery of disorder-specific situations proved to be a powerful tool to investigate dysfunctional threat processing in anxiety disorders. The current functional magnetic resonance imaging (fMRI) study aimed at investigating brain activation in PD patients during disorder-related script-driven imagery. Seventeen PD patients and seventeen healthy controls (HC) were exposed to newly developed disorder-related and neutral narrative scripts while brain activation was measured with fMRI. Participants were encouraged to imagine the narrative scripts as vividly as possible and they rated their script-induced emotional states after the scanning session. PD patients rated disorder-related scripts as more arousing, unpleasant and anxiety-inducing as compared to HC. Patients relative to HC showed elevated activity in the right amygdala and the brainstem as well as decreased activity in the rostral anterior cingulate cortex, and the medial and lateral prefrontal cortex to disorder-related vs. neutral scripts. The results suggest altered amygdala/ brainstem and prefrontal cortex engagement and point towards the recruitment of brain networks with opposed activation patterns in PD patients during script-driven imagery.

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., (Copyright © 2018. Published by Elsevier B.V.)

Preclinical studies point to a pivotal role of the orexin 1 (OX 1 ) 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.