Panic disorder (PD) is characterized by prolonged anxiety about panic attacks, significantly impairing social functioning. Despite this impact, resting-state brain function anomalies in PD are insufficiently understood. We conducted a data-driven investigation of resting-state functional connectivity (rsFC) in PD.

MRI scans and clinical assessments were performed on PD patients and healthy controls (HCs). Differences in rsFC were analyzed using the cluster-wise analysis of 9045 connections among 135 regions across the brain. For significant clusters, correlations between rsFC and clinical scores for panic and anxiety symptoms were examined.

Thirty-nine patients and 44 HCs were included in the analyses. A significant cluster-level difference in rsFC was observed between groups, involving connections between the medial occipital region and the paracingulate gyrus within the anterior cingulate cortex (ACC). In this cluster, PD patients exhibited higher rsFC in 11 connections, with eight of these showing positive correlations with State-Trait Anxiety Inventory scores.

The comprehensive analysis of 9045 connections may have diluted statistical power, potentially obscuring other relevant connections.

Increased rsFC between the medial occipital region and the ACC was observed in PD. This suggests that anxiety-evoking visual imagery generated in the occipital lobe may disproportionately influence self-referential thought process mediated by the ACC. Interventions targeting visual imagery may help alleviate daily anxiety in PD patients.

Anxiety sensitivity (AS) - the tendency to perceive benign physiological stimuli as harmful - is a risk factor for anxiety disorders. Cross-sectionally, AS has been linked to increased negative > neutral neural activity in key nodes implicated in threat detection and interoceptive - i.e., the amygdala (AMYG) and insula (INS). Examining the unique contributions of AMYG-INS blood‑oxygen-level-dependent (BOLD) response to neutral and negative stimuli to the prospective prediction of AS could increase understanding of the factors predisposing individuals to worsening AS over time.

Forty-six participants, including 33 patients with mixed internalizing disorders, underwent fMRI scans to assess insula and amygdala activation in response to neutral and negative pictures. AS was measured via self-report at baseline (Time 1) and approximately 1.5 years later (Time 2). We assessed whether BOLD to negative and/or neutral pictures at baseline predicted changes in AS over time.

Greater insula and amygdala activation in response to neutral pictures at baseline predicted higher AS 1.5 years later, controlling for initial levels of AS and BOLD response to negative pictures. Cross-sectionally, greater insula and amygdala activation in response to negative pictures relative to neutral pictures was associated with higher Time 1 AS.

Heightened AMYG-INS BOLD to benign stimuli precedes and may place individuals at risk for increased AS. Once established, heightened AS appears to be characterized by a neural pattern that is more often-observed in the internalizing disorders - i.e., exaggerated response to negative (> neutral) stimuli.

In the aftermath of psychological trauma, many individuals experience perturbations in interoception, a term that broadly references the ability to accurately detect body signals and integrate these signals with emotional states. These interoceptive disruptions can manifest in different ways, including blunting or amplification of sensitivity to internal physiological signals. In this chapter we review extant neurophysiological research on interoception in trauma-exposed populations, with a particular focus on the effects of chronic interpersonal trauma, such as childhood maltreatment and racial discrimination. We explore research that used different types of interoceptive assays, from self-report measures to electrophysiological and neuroimaging tools to characterize the disruptions in pain perception, interoceptive acuity, and physiological responses that may arise after a traumatic event. Finally, we discuss interventions that are designed to target interoceptive mechanisms, from exposure-based therapies to mindfulness-based practices, as well as future directions in trauma interoception research.

Given the high rate of trauma exposure among the general population, it is important to delineate the risk factors for post-traumatic stress disorder (PTSD). While historically implicated in panic disorder, anxiety sensitivity is increasingly found to play a role in PTSD. The present review investigated the size of the relationship between anxiety sensitivity and PTSD symptoms among trauma exposed adults. A systematic search on multiple electronic databases (PTSDpubs, CINAHL, MEDLINE and PsycINFO) generated a total of 1025 records, among which 52 (n = 15173) met study inclusion criteria and were included in our random effects meta-analysis. Our results indicated a medium effect size (r = .46, 95% CI =.41,.50) for the relationship between anxiety sensitivity and PTSD symptoms. There was significant between-study heterogeneity. Furthermore, sub-group analyses revealed that study design (cross-sectional vs. longitudinal) may significantly moderate the association between anxiety sensitivity and PTSD severity. No moderation effect was found for assessment of PTSD through interview versus questionnaire, interpersonal versus non-interpersonal trauma, or low versus high study quality. Such patterns of results are consistent with cognitive models of PTSD. Clinical implications, strengths and limitations of the review were discussed.

Suicide has a profound impact on individuals, families, and society. One prominent, if understudied, risk factor for suicide is anxiety. More than 70% of people with at least one suicide attempt meet diagnostic criteria for an anxiety disorder. There are several limitations to exploring the associations between anxiety and suicide using diagnosis-based classification systems. A better approach would be to consider transdiagnostic risk factors for anxiety.

Through a negative reinforcement model of suicide, anxiety sensitivity (AS) and intolerance of uncertainty (IU) appear to exacerbate the experience of unpleasant anxiety sensations and likely contribute to chronic suicide risk as well as acute suicidal acts. Although more research is needed to clarify the mechanisms through which AS and IU confer risk, brief interventions may offer an ideal suicide prevention strategy for anxious people.

Evidence of comparing neural network differences between anxiety disorder subtypes is limited, while it is crucial to reveal the pathogenesis of anxiety disorders. The present study aimed to investigate specific and common resting-state functional connectivity (FC) networks in generalized anxiety disorder (GAD), panic disorder (PD), and healthy controls (HC). We employed the gRAICAR algorithm to decompose the resting-state fMRI into independent components and align the components across 61 subjects (22 GAD, 18 PD and 21 HC). The default mode network and precuneus network exhibited GAD-specific aberrance, the anterior default mode network showed atypicality specific to PD, and the right fronto-parietal network showed aberrance common to GAD and PD. Between GAD-specific networks, FC between bilateral dorsolateral prefrontal cortex (DLPFC) was positively correlated with interoceptive sensitivity. In the common network, altered FCs between DLPFC and angular gyrus, and between orbitofrontal cortex and precuneus, were positively correlated with anxiety severity and interoceptive sensitivity. The pathological mechanism of PD could closely relate to the dysfunction of prefrontal cortex, while GAD could involve more extensive brain areas, which may be related to fear generalization.

Recent evidence implicates intensive panic control treatment (IPCT) - a full panic control treatment protocol compressed into a single weekend - as a viable alternative for Veterans with panic disorder who are unable or unwilling to commit to standard weekly cognitive behavioral therapy (CBT). However, no studies to date have examined pretreatment predictors of response to IPCT. Knowledge of such predictors may be important for understanding which Veterans are best suited for IPCT relative to standard CBT.

Participants were military Veterans with a primary diagnosis of panic disorder (N = 26) who participated in three open trials of IPCT. Pretreatment predictors were tested within linear regression models used to predict panic disorder severity at 2-week and 6-month follow-up assessments. Pretreatment predictors included: Panic disorder severity, agoraphobic avoidance, PTSD symptoms, anxiety sensitivity, and age.

Pretreatment symptoms of PTSD predicted reduced treatment response at 2-week but not 6-month follow-up, whereas pretreatment anxiety sensitivity predicted reduced response at 6-month but not 2-week follow-up.

Current findings are tempered by the exploratory nature of the analyses and a small sample.

Our study offers tentative evidence that success in IPCT may be linked to a distinct pretreatment profile relative to that of standard weekly therapy. These preliminary findings should be confirmed in larger studies that directly compare pretreatment predictors of intensive versus standard weekly CBT for panic disorder.

Early and accurate diagnosis of panic disorder with or without agoraphobia (PDA) is crucial to reducing disease burden and individual suffering. However, its diagnosis is challenging for lack of validated biomarkers. This study aimed to investigate whether radiomic features extracted from T1-weighted images (T1) of major fear-circuit structures (amygdala, insula, and anterior cingulate cortex [ACC]) could differentiate patients with PDA from healthy controls (HCs).

The 213 participants (93 PDA, 120 HCs) were allocated to training (n = 149) and test (n = 64) sets after undergoing magnetic resonance imaging. Radiomic features (n = 1498) were extracted from T1 of the studied structures. Machine learning models were trained after feature selection and then validated in the test set. SHapley Additive exPlanations (SHAP) explored the model interpretability.

We identified 29 radiomic features to differentiate participants with PDA from HCs. The area under the curve, accuracy, sensitivity, and specificity of the best performing radiomics model in the test set were 0.84 (95% confidence interval: 0.74-0.95), 81.3%, 75.0%, and 86.1%, respectively. The SHAP model explanation suggested that the energy features extracted from the bilateral long insula gyrus and central sulcus of the insula and right ACC were highly associated with the risk of PDA.

This was a cross-sectional study with a relatively small sample size, and the causality of changes in radiomic features and their biological and clinical meanings remained to be elucidated.

Our findings suggest that radiomic features from the fear-circuit structures could unveil hidden microstructural aberrations underlying the pathogenesis of PDA that could help identify PDA.

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.

Disrupted interoceptive processes are present in a range of psychiatric conditions, and there is a small but growing body of research on the role of interoception in obsessive-compulsive disorder (OCD). In this review, we outline dimensions of interoception and review current literature on the processing of internal bodily sensations within OCD. Investigations in OCD utilizing objective measures of interoception are limited and results mixed, however, the subjective experience of internal bodily sensations appears to be atypical and relate to specific patterns of symptom dimensions. Further, neuroimaging investigations suggest that interoception is related to core features of OCD, particularly sensory phenomena and disgust. Interoception is discussed in the context of treatment by presenting an overview of existing interventions and suggesting how modifications aimed at better targeting interoceptive processes could serve to optimize outcomes. Interoception represents a promising direction for multi-method research in OCD, which we expect, will prove useful for improving current interventions and identifying new treatment targets.

Burn survivors experience myriad associated symptoms such as pain, pruritus, fatigue, impaired motor strength, post-traumatic stress, depression, anxiety, and sleep disturbance. Many of these symptoms are common and remain chronic, despite current standard of care. One potential novel intervention to target these post burn symptoms is transcranial direct current stimulation (tDCS). tDCS is a non-invasive brain stimulation (NIBS) technique that modulates neural excitability of a specific target or neural network. The aim of this work is to review the neural circuits of the aforementioned clinical sequelae associated with burn injuries and to provide a scientific rationale for specific NIBS targets that can potentially treat these conditions. We ran a systematic review, following the PRISMA statement, of tDCS effects on burn symptoms. Only three studies matched our criteria. One was a feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury, one looked at the effects of tDCS to reduce pain anxiety during burn wound care, and one assessed the effects of tDCS to manage pain and pruritus in burn survivors. Current literature on NIBS in burn remains limited, only a few trials have been conducted. Based on our review and results in other populations suffering from similar symptoms as patients with burn injuries, three main areas were selected: the prefrontal region, the parietal area and the motor cortex. Based on the importance of the prefrontal cortex in the emotional component of pain and its implication in various psychosocial symptoms, targeting this region may represent the most promising target. Our review of the neural circuitry involved in post burn symptoms and suggested targeted areas for stimulation provide a spring board for future study initiatives.

Early trauma (ET) is a risk factor for adult psychiatric disorders. ET exposure is known to cause structural brain alterations, particularly in the fronto-temporo-limbic circuitry. ET-related effects on brain development may differ based on individual characteristics and cause different psychiatric outcomes. We investigated the interaction effect of ET exposure and panic disorder (PD) on cortical thickness.

Sixty-six participants with PD and 66 healthy controls were enrolled. High-resolution T1-weighted images were acquired, and a whole-brain vertex-based analysis was performed to estimate cortical thickness. The Early Trauma Inventory Self Report-Short Form, Anxiety Sensitivity Inventory-Revised, Panic Disorder Severity Scale, Beck Depression Inventory-II, and Beck Anxiety Inventory were administered.

There was a significant interaction between ET exposure and PD on the mean cortical thickness in the bilateral insula and right pars triangularis. An exploratory correlational analysis revealed a positive correlation between the mean cortical thickness in the left insula and severity of anxiety sensitivity to cardiovascular symptoms in participants with PD.

Our findings may be affected by recall bias because this study is limited by its retrospective cross-sectional design.

Our findings suggest that ET exposure may affect brain structures differently based on a diagnosis of PD. Furthermore, individual variations in brain alterations after ET may confer trait vulnerability that triggers the development of PD. Future longitudinal studies are warranted to elucidate the neurobiological mechanisms underlying ET and psychiatric outcomes.

This study aimed to examine the behavioral and neural correlates of facial emotion recognition in young women with subsyndromal panic disorder (SPD). In the experiment 15 non-medicated women with SPD and 17 matched healthy controls were tasked with recognizing angry, fearful, happy, and neutral facial expressions, and accuracy, reaction time (RT), and event-related potentials (ERPs) were recorded. Significant between-group differences in behavioral characteristics (accuracy of emotion recognition and RT) were not found, however, the SPD subjects demonstrated a slower response to fearful expressions compared to neutral and happy expressions. More distinct between-group differences were observed for the EPRs. The SPD subjects demonstrated increased amplitudes of the P100 ERP component in the occipital area and the P200 component over the occipital and temporal regions. In the frontal regions the SPD group showed a greater amplitude of the N200 component and also an increased negativity 350-450 ms after stimulus presentation. According to the dipole source modeling data, the SPD subjects showed enhanced activation in the extra-striate cortex which increased in intensity when angry and fearful faces were presented. Thus, young women with SPD which manifested in infrequent panic attacks showed significant alterations in ERP characteristics of emotional processing, which may be considered as a more sensitive indicator of early-stage panic disorder than the observed behavioral measures.

Panic Disorder (PD) is mainly characterized by recurrent unexpected panic attacks. Although the presence of emotional functioning deficits in PD is well established, their neuronal bases are still less known. Therefore, in this review, we aim to summarize the available functional Magnetic Resonance Imaging (fMRI) studies investigating the neural correlates associated with the processing of facial emotional expressions in patients with PD.

A comprehensive search on PubMed was performed and 10 fMRI studies meeting our inclusion criteria were included in this review.

The majority of the studies reported selective deficits in key brain regions within the prefronto-limbic network in PD patients. Specifically, a mixed picture of hyperactivation and hypoactivation patterns were observed in limbic regions, including the amygdala and the anterior cingulate cortex (ACC), as well as in areas within the prefrontal cortex (PFC), either during negative or positive valenced stimuli, as compared to healthy controls (HC) or other anxiety disorders.

The limited number of studies and the clinical and methodological heterogeneity make it difficult to draw definite conclusions on the neural mechanism of emotional processing associated with PD.

Although the results of the available evidence suggest the presence of selective dysfunctions in regions within the cortico-limbic network in PD patients during processing of emotional stimuli, the direction of these abnormalities is still unclear. Therefore, future larger and more homogeneous studies are needed to elucidate the neural mechanisms underpinning the emotional processing dysfunctions often observed in PD patients.

Anxiety sensitivity (AS) is a multidimensional construct associated with the etiology and maintenance of panic disorder (PD) symptoms. However, only a few studies have evaluated whether cognitive-behavioral group therapy (CBGT) can modify the condition. The objective of this study was to evaluate the impact of CBGT on AS in patients with PD and to analyze AS and its dimensions as predictors of response to CBGT. In the present clinical trial, an intervention group (n = 37) attended 12 CBGT sessions, while a control group (n = 52) did not receive any intervention. The severity of symptoms and of AS were evaluated before and after CBGT in the intervention group and once in the control group. Significant improvement occurred in all specific PD symptoms and in general anxiety and depressive symptoms. Furthermore, AS scores reduced significantly after intervention. This study confirmed that AS is higher in patients with more severe PD. The effectiveness of CBGT for reducing the physical, cognitive, and social dimensions of AS was also observed, supporting the hypothesis of a positive impact of therapy.

In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.

We sought to define the role of central NE transmission in neophilic and neophobic behaviors.

We assessed dopamine β-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions.

Dbh -/- mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/- mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/- mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala.

These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.

Anxiety sensitivity (AS), or the fear of anxious arousal, is a transdiagnostic risk factor predictive of a wide variety of affective disorders. Whereas AS is widely studied via self-report, the neurophysiological correlates of AS are poorly understood. One specific issue this may help resolve is well-established gender differences in mean levels of AS. The current study evaluated late positive potential (LPP) for images designed to target AS during an emotional picture viewing paradigm. Structural equation modeling was used to examine convergent and discriminant validity for self-report AS and the LPP for AS images, considering gender as a potential moderator. Analyses were conducted in an at-risk sample of 251 community adults (M age = 35.47, SD = 15.95; 56.2% female; 53.6% meeting for a primary Axis I anxiety or related disorder). Findings indicated that the AS image LPP was significantly, uniquely associated with self-report AS, controlling for the LPP for unpleasant images, in females only. Mean levels of AS self-report as well as the AS image LPP were higher in females than in males. These findings provide initial support for the AS image LPP as a useful neurophysiological correlate of AS self-report in females. These findings also provide support for a biological cause for gender differences in AS. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The core concept for pathophysiology in panic disorder (PD) is the fear network model (FNM). The alterations in FNM might be linked with disturbances in the autonomic nervous system (ANS), which is a common phenomenon in PD. The traditional FNM included the frontal and limbic regions, which were dysregulated in the feedback mechanism for cognitive control of frontal lobe over the primitive response of limbic system. The exaggerated responses of limbic system are also associated with dysregulation in the neurotransmitter system. The neuroimaging studies also corresponded to FNM concept. However, more extended areas of FNM have been discovered in recent imaging studies, such as sensory regions of occipital, parietal cortex and temporal cortex and insula. The insula might integrate the filtered sensory information via thalamus from the visuospatial and other sensory modalities related to occipital, parietal and temporal lobes. In this review article, the traditional and advanced FNM would be discussed. I would also focus on the current evidences of insula, temporal, parietal and occipital lobes in the pathophysiology. In addition, the white matter and functional connectome studies would be reviewed to support the concept of advanced FNM. An emerging dysregulation model of fronto-limbic-insula and temporooccipito-parietal areas might be revealed according to the combined results of recent neuroimaging studies. The future delineation of advanced FNM model can be beneficial from more extensive and advanced studies focusing on the additional sensory regions of occipital, parietal and temporal cortex to confirm the role of advanced FNM in the pathophysiology of PD.

Suicide is a global public health concern. To inform the prevention and treatment of suicidality, it is crucial to identify transdiagnostic vulnerability factors for suicide and suicide-related conditions. One candidate factor is anxiety sensitivity (AS)-the fear of anxiety-related sensations-which has been implicated in the pathogenesis of a host of mental health outcomes, including suicidal thoughts and behaviors. Importantly, AS is distinct from trait anxiety and negative affectivity, highlighting its potential incremental utility in the understanding of psychopathology. Despite a burgeoning body of literature demonstrating that AS is linked to suicidal thoughts and behaviors, this research has yet to be synthesized.

This meta-analysis includes 33 articles representing 34 nonredundant samples (N = 14,002) that examined at least one relationship between AS global or subfactor (i.e., cognitive, physical, social) scores and suicidal ideation and/or suicide risk.

Findings revealed small-to-moderate and moderate associations between global AS and suicidal ideation (r = .24, 95% confidence interval (CI): [.21, .26], p < .001) and suicide risk (r = .35, 95% CI [.31, .38], p < .001), respectively. All AS subfactors evinced significant associations with suicidal ideation (rs = .13-.24) and suicide risk (rs = .22-.32).

AS is related to suicidal ideation and global suicide risk. Research is needed to disentangle AS from other indices of distress in the prediction of suicidal thoughts and behaviors. Theoretical and clinical implications of these findings are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Increased automatic processing of threat-related stimuli has been proposed as a key element in panic disorder. Little is known about the neural basis of automatic processing, in particular to task-irrelevant, panic-related, ecologically valid stimuli, or about the association between brain activation and symptomatology in patients with panic disorder.

The present event-related functional MRI (fMRI) study compared brain responses to task-irrelevant, panic-related and neutral visual stimuli in medication-free patients with panic disorder and healthy controls. Panic-related and neutral scenes were presented while participants performed a spatially nonoverlapping bar orientation task. Correlation analyses investigated the association between brain responses and panic-related aspects of symptomatology, measured using the Anxiety Sensitivity Index (ASI).

We included 26 patients with panic disorder and 26 heatlhy controls in our analysis. Compared with controls, patients with panic disorder showed elevated activation in the amygdala, brainstem, thalamus, insula, anterior cingulate cortex and midcingulate cortex in response to panic-related versus neutral task-irrelevant stimuli. Furthermore, fear of cardiovascular symptoms (a subcomponent of the ASI) was associated with insula activation, whereas fear of respiratory symptoms was associated with brainstem hyperactivation in patients with panic disorder.

The additional implementation of measures of autonomic activation, such as pupil diameter, heart rate, or electrodermal activity, would have been informative during the fMRI scan as well as during the rating procedure.

Results reveal a neural network involved in the processing of panic-related distractor stimuli in patients with panic disorder and suggest an automatic weighting of panic-related information depending on the magnitude of cardiovascular and respiratory symptoms. Insula and brainstem activations show function-related associations with specific components of panic symptomatology.

Anxiety disorders are the most common mental health problem in the world and also claim the highest health care cost among various neuropsychiatric disorders. Anxiety disorders have a chronic and recurrent course and cause significantly negative impacts on patients' social, personal, and occupational functioning as well as quality of life. Despite their high prevalence rates, anxiety disorders have often been under-diagnosed or misdiagnosed, and consequently under-treated. Even with the correct diagnosis, anxiety disorders are known to be difficult to treat successfully. In order to implement better strategies in diagnosis, prognosis, treatment decision, and early prevention for anxiety disorders, tremendous efforts have been put into studies using genetic and neuroimaging techniques to advance our understandings of the underlying biological mechanisms. In addition to anxiety disorders including panic disorder, generalised anxiety disorder (GAD), specific phobias, social anxiety disorders (SAD), due to overlapping symptom dimensions, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) (which were removed from the anxiety disorder category in DSM-5 to become separate categories) are also included for review of relevant genetic and neuroimaging findings. Although the number of genetic or neuroimaging studies focusing on anxiety disorders is relatively small compare to other psychiatric disorders such as psychotic disorders or mood disorders, various structural abnormalities in the grey or white matter, functional alterations of activity during resting-state or task conditions, molecular changes of neurotransmitter receptors or transporters, and genetic associations have all been reported. With continuing effort, further genetic and neuroimaging research may potentially lead to clinically useful biomarkers for the prevention, diagnosis, and management of these disorders.

To provide an overview of the current research in the functional neuroanatomy of panic disorder.

Panic disorder (PD) is a frequent psychiatric disease. Gorman et al (1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear- and anxiety-related responses are mediated by a so-called "fear network" which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies (from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics.

We noted that many neuroimaging studies have reinforced the role of the "fear network" regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex (ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al (2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is "imaging genetics". Imaging genetic studies are designed to evaluate the impact of genetic variations (polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransMEMbrane protein (TMEM123D), and amiloride-sensitive cation channel 2 (ACCN2) genes.

In light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.

Different degrees of threat predictability are thought to induce either phasic fear or sustained anxiety. Maladaptive, sustained anxious apprehension is thought to result in overgeneralization of anxiety and thereby to contribute to the development of anxiety disorders. Therefore, differences in threat predictability have been associated with pathological states of anxiety with specific phobia (SP) representing phasic fear as heightened response to predictable threat, while panic disorder (PD) is characterized by sustained anxiety (unpredictable threat) and, as a consequence, overgeneralization of fear. The present study aimed to delineate commonalities and differences in the neural substrates of the impact of threat predictability on affective processing in these two anxiety disorders. Twenty PD patients, 20 SP patients and 20 non-anxious control subjects were investigated with an adapted NPU-design (no, predictable, unpredictable threat) using whole-head magnetoencephalography (MEG). Group independent neural activity in the right dlPFC increased with decreasing threat predictability. PD patients showed a sustained hyperactivation of the vmPFC under threat and safety conditions. The magnitude of hyperactivation was inversely correlated with PDs subjective arousal and anxiety sensitivity. Both PD and SP patients revealed decreased parietal processing of affective stimuli. Findings indicate overgeneralization between threat and safety conditions and increased need for emotion regulation via the vmPFC in PD, but not SP patients. Both anxiety disorders showed decreased activation in parietal networks possibly indicating attentional avoidance of affective stimuli. Present results complement findings from fear conditioning studies and underline overgeneralization of fear, particularly in PD.

Anxiety sensitivity (AS) refers to a fear of anxiety-related sensations and is a dispositional variable especially elevated in patients with panic disorder (PD). Although several functional imaging studies of AS in patients with PD have suggested the presence of altered neural activity in paralimbic areas such as the insula, no study has investigated white matter (WM) alterations in patients with PD in relation to AS. The objective of this study was to investigate the WM correlates of AS in patients with PD.

One-hundred and twelve right-handed patients with PD and 48 healthy control (HC) subjects were enrolled in this study. The Anxiety Sensitivity Inventory-Revised (ASI-R), the Panic Disorder Severity Scale (PDSS), the Albany Panic and Phobia Questionnaire (APPQ), the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI) were administered. Tract-based spatial statistics were used for diffusion tensor magnetic resonance imaging analysis.

Among the patients with PD, the ASI-R total scores were significantly correlated with the fractional anisotropy values of the WM regions near the insula, the splenium of the corpus callosum, the tapetum, the fornix/stria terminalis, the posterior limb of the internal capsule, the retrolenticular part of the internal capsule, the posterior thalamic radiation, the sagittal striatum, and the posterior corona radiata located in temporo-parieto-limbic regions and are involved in interoceptive processing (p<0.01; threshold-free cluster enhancement [TFCE]-corrected). These WM regions were also significantly correlated with the APPQ interoceptive avoidance subscale and BDI scores in patients with PD (p<0.01, TFCE-corrected). Correlation analysis among the HC subjects revealed no significant findings.

There has been no comparative study on the structural neural correlates of AS in PD.

The current study suggests that the WM correlates of AS in patients with PD may be associated with the insula and the adjacent temporo-parieto-limbic WM regions, which may play important roles in interoceptive processing in the brain and in depression in PD.

Panic disorder is an often chronic and impairing human anxiety syndrome, which frequently results in serious psychiatric and medical comorbidities. Although, to date, there have been many advances in the diagnosis and treatment of panic disorder, its pathophysiology still remains to be elucidated. In this review, recent evidence for a neurobiological basis of panic disorder is reviewed with particular attention to risk factors such as genetic vulnerability, chronic stress, and temperament. In addition, neuroimaging data are reviewed which provides support for the concept of panic disorder as a fear network disorder. The potential impact of the National Institute of Mental Health Research Domain Criteria constructs of acute and chronic threats responses and their implications for the neurobiology of panic disorder are also discussed.

Panic disorder is commonly prevalent in the population, but the treatment response for panic disorder in clinical practice is much less effective than that in our imagination. Increasing evidence suggested existence of a chronic or remitting-relapsing clinical course in panic disorder. In this systematic review, we re-examine the definition of treatment-resistant panic disorder, and present the potential risk factors related to the treatment resistance, including the characteristics of panic disorder, other psychiatric and physical comorbidities, and psychosocial stresses. Furthermore, we summarize the potential pathophysiologies, such as genetic susceptibility, altered brain functioning, brain-derived neurotrophic factor, and long-term inflammation, to explain the treatment resistance. Finally, we conclude the current therapeutic strategies for treating treatment-resistant panic disorder from pharmacological and non-pharmacological views.

Facilitated processing of interoceptive and exteroceptive information in the salience network is suggested to promote the development of anxiety and anxiety disorders. Here, it was investigated whether the adenosine 2 A receptor gene (ADORA2A) 1976T/C (rs5751876) variant - previously associated with anxiety disorders and anxiety-related phenotypes as well as general attentional efficiency -was involved in the regulation of this network. In detail, fMRI recordings of 65 healthy participants (female=35) were analyzed regarding ADORA2A genotype effects on brain connectivity related to (1) interoceptive processing in terms of functional connectivity resting-state fMRI, and (2) exteroceptive processing using dynamic causal modeling in task-based fMRI. In a subsample, cardiac interoceptive accuracy was furthermore measured via the Mental Tracking Task. ADORA2A genotype was found to modulate a fronto-insular network at rest (interoceptive processing) and while performing an executive control task (exteroceptive processing). Across both modalities, the ADORA2A TT risk genotype was associated with increased connectivity between the insula and the prefrontal cortex. The strength in connectivity correlated with interoceptive accuracy. It is concluded that alterations in fronto-insular connectivity are modulated by both the adenosinergic system and interoceptive accuracy. Thus, fronto-insular connectivity in synopsis with ADORA2A genotypic information could serve as combined biomarkers for personalized treatment approaches in anxiety disorders targeting exteroceptive and interoceptive dysfunction.

Migraine is a highly prevalent and disabling neurological disorder associated with a wide range of psychiatric comorbidities. In this manuscript, we provide an overview of the link between migraine and several comorbid psychiatric disorders, including depression, anxiety and post-traumatic stress disorder. We present data on psychiatric risk factors for migraine chronification. We discuss the evidence, theories and methods, such as brain functional imaging, to explain the pathophysiological links between migraine and psychiatric disorders. Finally, we provide an overview of the treatment considerations for treating migraine with psychiatric comorbidities. In conclusion, a review of the literature demonstrates the wide variety of psychiatric comorbidities with migraine. However, more research is needed to elucidate the neurocircuitry underlying the association between migraine and the comorbid psychiatric conditions and to determine the most effective treatment for migraine with psychiatric comorbidity.

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders.