Neural correlates of anxiety sensitivity in panic disorder: A functional magnetic resonance imaging study
Introduction
Panic disorder (PD) has been associated with several dysfunctional neuropsychological dimensions, among which anxiety sensitivity seems to be a unique feature of the disorder. Amplification of somatic sensations with subsequent dysfunctional cognitive appraisal, and a significant bias toward a danger-related and catastrophizing interpretation, is considered a core neuropsychological construct in anxiety disorders including panic disorder (Clark, 1986). Anxiety sensitivity (AS) refers to a tendency to fear anxiety-related sensations (Reiss and McNally, 1985), and it is characterised by fear amplification in response to stimuli that elicit anxiety (Reiss, 1991). High AS individuals maintain the belief that experiencing anxiety or fear will cause severe negative consequences (i.e., heart attack), are hypervigilant to stimuli that signal anxiety (i.e., increased heart rate), worry about becoming anxious, and avoid stimuli that provoke anxiety (Reiss et al., 1986, McNally, 2002). AS has been associated with PD (Foot and Koszycki, 2004, White et al., 2006, Naragon-Gainey, 2010), and the level of AS is greater among individuals with anxiety disorders in general (i.e., PD, social phobia, specific phobia, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and agoraphobia without panic) as compared with nonclinical controls (Olatunji and Wolitzky-Taylor, 2009). However, prospective studies have shown that AS specifically predicts the onset of panic (Benitez et al., 2009) and that PD patients significantly differ from other anxiety disorders in AS levels, suggesting unique features of AS in PD (Olatunji and Wolitzky-Taylor, 2009).
Different studies have identified deficits regarding emotion processing in PD (Galderisi et al., 2008, Cucchi et al., 2012), including the tendency to interpret ambiguous stimuli as threatening, and a bias toward somatic concerns in stressful situations (Clark, 1986). Brain-imaging studies of the neural correlates of human emotional processing, together with structural data from human and animal research, identified a network of structures that constitute the neural circuitry for emotions. The circuit includes the amygdala, insula, cingulate and prefrontal cortex (PFC), which interact to identify the emotional significance of the stimuli and to generate and regulate affective states (Phillips et al., 2003a, Phillips et al., 2003b). This network can be studied with functional magnetic resonance imaging (fMRI) paradigms, which can be used to examine the effective connectivity of the amygdala and its activation in response to negative facial expressions (Stein et al., 2007a). Increased activation of regions pertaining to this network has been observed across a range of anxiety diagnoses (post-traumatic stress disorder, social anxiety disorders, specific phobia and panic disorder) (Sakai et al., 2005; Britton and Rauch, 2008), and recruitment of these regions appears to be central to different self-preservation behaviours (i.e., frozen with fear; fight or flight). Moreover, the insula and the ACC, together with midbrain periaqueductal gray matter, have been suggested to be involved in the pathophysiology of panic disorder (Graeff and Del-Ben, 2008). However, responses in this circuit have varied depending on the paradigm used and the specific state explored. Hyperactivity of the amygdala and hypoactivity of the ACC have been found in anticipatory anxiety of a chemical challenge that may trigger panic attack (Boshuisen et al., 2002), while increased activity of the ACC has been observed during imagination of anxiogenic situations (Bystritsky et al., 2001). Hyperactivity of the amygdala has also been reported during emotional conflict (Chechko et al., 2009) and spontaneous panic attacks (Pfleiderer et al., 2007, Dresler et al., 2011), while hypoactivation has been shown in response to angry, fearful, happy and neutral faces (Pillay et al., 2006, Demenescu et al., 2013). A fear-conditioning task led to increased activity in the amygdala, subgenual cingulate, and midbrain structures (Tuescher et al., 2011), while activation in the frontal cortex has been observed for differential conditioning (Lueken et al., 2014). Finally increased activity in the prefrontal cortex, hippocampus and cingulate cortex has been reported (Ball et al., 2013, Dresler et al., 2013).
Fear-conditioning paradigms in panic disorder lead to increased activation in this network during a safety condition, suggesting that a network that signals fear is incorrectly activated (Tuescher et al., 2011). Changes in brain activation in cortico-limbic structures follow successful treatment with cognitive behavioural therapy (CBT), in particular, an inhibitory functional coupling between the ACC and the amygdala was found to be associated with response to treatment (Lueken et al., 2013).
Abnormalities in activity in these brain areas may then represent the core neural correlates of the psychopathology of panic disorder (Holzschneider and Mulert, 2011). Contrasting results have been reported in relation to the neural correlates of AS in healthy subjects. AS has been positively associated with activity in the insula (Stein et al., 2007b, Killgore et al., 2011) and ACC (Ball et al., 2012) during emotional processing, while no correlation between AS and brain activation has been observed during affective uncertainty processing (Simmons et al., 2008). A negative association between AS and neural responses to fearful faces compared with neutral faces has been found in the inferior parietal cortex, prefrontal cortex, insula, and ACC (Schafer et al., 2009).
Only one study, to our best knowledge, investigated the neural correlates of AS in panic disorder, and that study found a positive correlation between AS and brain activation in the midbrain during fear conditioning (Lueken et al., 2014).
Because PD is clinically characterized by AS and that, from a neuroimaging perspective, previous studies showed functional abnormalities in brain regions related to this construct, the aim of the study was to investigate whether neural activity in response to emotional stimuli in the cortico-limbic network was associated to AS in a sample of patients affected by PD.
Section snippets
Sample
We studied 18 outpatients (5 males and 13 females) affected by panic disorder with agoraphobia (DSM-IV criteria, SCID-I interview), seen at San Raffaele Turro Hospital. Characteristics of the patients were as follows: mean age 30.5±10.30 years; Panic Associated Symptoms Scale total score 22.11±8.78; education 12.44±3.40 years; age at onset 28±12.97 years; duration of illness 5.75±6.61 years; Clinical Global Impressions Scale (CGI) score 5.23±1.03. Twelve out of 18 patients suffered from
Results
Clinical and demographical data are (mean±SD) as follows: age at onset of illness 27.28±10.64 years, and ASI score 34±11.19. A significant difference was observed between reaction times for shapes and faces (shapes: 4.59±0.88; faces: 5.53±1.26; t=−2.52, p=0.016).
We observed a main effect of the task in two clusters within the insula (MNI coordinates −28 −18 22; −46 6 6), an effect that did not survive correction for multiple comparisons. No differences were found in the processing of fearful
Discussion
The main result of the present study is a correlation between AS and brain activity in core structures involved in emotion processing in panic disorder. Higher levels of AS are associated to greater activations in ACC and insula in response to emotional faces. The dorsal ACC (dACC) and the adjacent dorsomedial PFC (dmPFC) are particularly involved in the appraisal and expression of fear (Etkin et al., 2011) but also in evaluative judgment and anticipation of emotional stimuli (Blackwood et al.,
Role of funding source
None of the authors have financial disclosures pertinent to the contents of the article. Our research unit received research grants from the Italian Ministry of University and Scientific Research (RF-2011-02349921), from the Italian Ministry of Health (RF-2011-02350980), and from the European Union (FP7 Grant 222963).
Conflict of interest
No conflict of interest.
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