Christiane A. Pané-Farré

Brain activation during anticipation of interoceptive threat

The current study investigated the neural networks activated during the anticipation of potentially threatening body symptoms evoked by a guided hyperventilation task in a group of participants reporting either high or low fear of unexplained somatic sensations. 15 subjects reporting high and 14 subjects reporting low fear of somatic symptoms first learned that one of two cues predicted the occurrence of a hyperventilation task reliably producing body symptoms in all participants that were rated as more intense and unpleasant in the high fear group. During anticipation of unpleasant symptoms, high fear participants reported more intense body symptoms and showed potentiation of the startle reflex. After this learning session, participants were taken into the fMRI where the same cues either predicted the occurrence of hyperventilation or normoventilation, although the task was never performed in the scanner. During anticipation of hyperventilation all participants showed an increased activation of anterior insula/orbitofrontal cortex and rostral parts of the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex (dACC/dmPFC). Brain activation of high compared to low fear participants differed in two ways. First, high fear participants showed an overall stronger activation of this network during threat and safe conditions indexing stronger anxious apprehension during the entire context. Second, while low fear participants no longer responded with stronger activation to the threat cue after experiencing that the hyperventilation challenge did not follow this cue, high fear participants continued to show stronger activation of the network to this cue. Activation of the rostral dACC/dmPFC was significantly correlated with reported fear of somatic symptoms. These data demonstrate that anticipation of interoceptive threat activates the same network that has been found to be active during anticipation of exteroceptive threat cues. Thus, the current paradigm might provide an innovative method to study anxious apprehension and treatment effects in patients with panic disorder.

Dynamics of Defensive Reactivity in Patients with Panic Disorder and Agoraphobia: Implications for the Etiology of Panic Disorder

BACKGROUND The learning perspective of panic disorder distinguishes between acute panic and anxious apprehension as distinct emotional states. Following animal models, these clinical entities reflect different stages of defensive reactivity depending upon the imminence of interoceptive or exteroceptive threat cues. The current study tested this model by investigating the dynamics of defensive reactivity in a large group of patients with panic disorder and agoraphobia (PD/AG). METHODS Three hundred forty-five PD/AG patients participated in a standardized behavioral avoidance test (being entrapped in a small, dark chamber for 10 minutes). Defense reactivity was assessed measuring avoidance and escape behavior, self-reports of anxiety and panic symptoms, autonomic arousal (heart rate and skin conductance), and potentiation of the startle reflex before and during exposure of the behavioral avoidance test. RESULTS Panic disorder and agoraphobia patients differed substantially in their defensive reactivity. While 31.6% of the patients showed strong anxious apprehension during this task (as indexed by increased reports of anxiety, elevated physiological arousal, and startle potentiation), 20.9% of the patients escaped from the test chamber. Active escape was initiated at the peak of the autonomic surge accompanied by an inhibition of the startle response as predicted by the animal model. These physiological responses resembled the pattern observed during the 34 reported panic attacks. CONCLUSIONS We found evidence that defensive reactivity in PD/AG patients is dynamically organized ranging from anxious apprehension to panic with increasing proximity of interoceptive threat. These data support the learning perspective of panic disorder.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic–pituitary–adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

Brain dynamics of visual attention during anticipation and encoding of threat- and safe-cues in spider-phobic individuals

This study systematically investigated the sensitivity of the phobic attention system by measuring event-related potentials (ERPs) in spider-phobic and non-phobic volunteers in a context where spider and neutral pictures were presented (phobic threat condition) and in contexts where no phobic but unpleasant and neutral or only neutral pictures were displayed (phobia-irrelevant conditions). In a between-group study, participants were assigned to phobia-irrelevant conditions either before or after the exposure to spider pictures (pre-exposure vs post-exposure participants). Additionally, each picture was preceded by a fixation cross presented in one of three different colors that were informative about the category of an upcoming picture. In the phobic threat condition, spider-phobic participants showed a larger P1 than controls for all pictures and signal cues. Moreover, individuals with spider phobia who were sensitized by the exposure to phobic stimuli (i.e. post-exposure participants) responded with an increased P1 also in phobia-irrelevant conditions. In contrast, no group differences between spider-phobic and non-phobic individuals were observed in the P1-amplitudes during viewing of phobia-irrelevant stimuli in the pre-exposure group. In addition, cues signaling neutral pictures elicited decreased stimulus-preceding negativity (SPN) compared with cues signaling emotional pictures. Moreover, emotional pictures and cues signaling emotional pictures evoked larger early posterior negativity (EPN) and late positive potential (LPP) than neutral stimuli. Spider phobics showed greater selective attention effects than controls for phobia-relevant pictures (increased EPN and LPP) and cues (increased LPP and SPN). Increased sensitization of the attention system observed in spider-phobic individuals might facilitate fear conditioning and promote generalization of fear playing an important role in the maintenance of anxiety disorders.

Induction of dyspnea evokes increased anxiety and maladaptive breathing in individuals with high anxiety sensitivity and suffocation fear

Although respiratory symptoms are relevant for diagnosis and etiology of panic disorder, anxiety responses and breathing behavior evoked by induction of dyspnea have rarely been studied. Therefore, dyspnea sensations and affective evaluations evoked by inspiratory resistive loads of different intensities were first assessed in 23 individuals with high versus 24 participants with low anxiety sensitivity (AS). High AS participants with high fear of suffocation rated loads of the same physical intensity as more unpleasant and reported more intense feelings of dyspnea and more respiratory and panic symptoms than low AS individuals. In the second experiment assessing physiological responses to physically comparable loads, high suffocation fear participants showed an increase in minute ventilation to compensate for fear-induced air hunger. This ventilation behavior results in increased frequency of dyspnea sensations, thus increasing fear of suffocation.

When the threat comes from inside the body: A neuroscience based learning perspective of the etiology of panic disorder

Unexpected, recurrent panic attacks and anxious apprehension are two distinct emotional phenomena that constitute the core symptoms for diagnosing panic disorder. Taking a neuroscience perspective the current review paper presents both epidemiological and experimental psychophysiological evidence suggesting that panic attacks can be conceptualized as an unconditioned circa defense response pattern to intense internal threat stimuli, characterized by strong autonomic surge and escape behavior and abnormal plastic changes of the brain. Anxious apprehension develops after the experience of such severe panic attacks as conditioned responses to mild body symptoms. Theoretically these conditioned fear responses can be considered as post-encounter defense characterized by increased selective attention, increased threat appraisal and defensive freezing and startle potentiation evidencing altered brain circuits evoked by mild body symptoms. Agoraphobic avoidance starts very early during the defensive cascade and can be conceived as motivated behavior driven by the incentive to be in a safe context that is under control of the individual.

Modulation of the blink reflex and P3 component of the startle response during an interoceptive challenge

The blink reflex component of the startle response is potentiated during processing of exteroceptive unpleasant stimuli. In contrast, blink magnitudes are often inhibited during interoceptive challenges. We measured respiration, blink magnitudes, and the P3 component to the acoustic startle probes in 34 participants while breathing against a mild resistance (mask-with-tubing) compared to breathing with no mask. Breathing through a mask with tubing resulted in increased inspiratory resistance as indicated by increased flow rate and tidal volume, a compensatory breathing pattern. Blink magnitudes to probes presented during the mask-with-tubing condition were inhibited compared to no-mask. Likewise, the probe P3 component was smaller during breathing through a mild resistance. These data suggest that startle inhibition during interoceptive challenges might be due to a shift in attention towards the mildly unpleasant interoceptive stimuli.

Modulation of the ERP repetition effects during exposure to phobia-relevant and other affective pictures in spider phobia

In the present study, dense sensor event-related potentials were measured in spider-phobic individuals and non-anxious controls during incidental encoding of phobia-relevant spider and standard neutral, unpleasant and pleasant pictures. Stimulus repetition effects were assessed by presenting each picture twice--in the first and in the second half of the session. Repeated presentation of standard pleasant, unpleasant and neutral pictures resulted in a late ERP repetition effect that was similarly pronounced in both experimental groups and for all picture categories. Moreover, relative to non-fearful controls spider-phobic individuals showed an overall greater early ERP repetition effect starting at 180 ms after picture onset. At later stages of evaluative processing, repeated as compared with initial presentation of phobia-relevant spider pictures elicited reduced ERP amplitudes over centro-parietal sites (480-580 ms) in spider-phobic but not in control individuals. This pattern of results indicates that in small animal phobics long lasting exposure to their feared pictures leads to an increased mobilization of the perceptual analysis system, an effect that might help to improve emotional control and/or facilitate strategic avoidance of threat resulting in a diminished evaluative threat processing. This phobia-specific processing mechanism might prevent effective stimulus processing and hinder the habituation process during treatment.

Sub-threshold panic attacks and agoraphobic avoidance increase comorbidity of mental disorders: results from an adult general population sample.

Full-blown panic attacks are frequently associated with other mental disorders. Most comorbidity analyses did not discriminate between isolated panic attacks vs. panic attacks that occurred in the context of a panic disorder and rarely evaluated the impact of comorbid agoraphobia. Moreover, there are no larger scale epidemiological studies regarding the influence of sub-threshold panic attacks. 4075 German-speaking respondents aged 18-64 were interviewed using the fully structured Munich Composite International Diagnostic Interview. Limited symptom attacks, isolated panic attacks, and panic disorder were associated with other lifetime DSM-IV disorders with monotonically increasing odds and increasing tendency for multiple comorbidities across the three groups. The presence of agoraphobia was associated with more frequent comorbidity in all panic subgroups and also in persons who never experienced panic attacks. The present study suggests that populations with isolated or limited symptom should be carefully attended to in clinical practice, especially if agoraphobia is present.

When dyspnea gets worse: Suffocation fear and the dynamics of defensive respiratory responses to increasing interoceptive threat.

In patients with anxiety and/or respiratory diseases, body sensations, particularly from the respiratory system, may increase in intensity and aversiveness and thus lead into defensive action (e.g., escape) or panic. The processes, however, that might contribute to the culmination of symptoms and the switch into defensive action have not been well understood yet. The current study aimed at evaluating an experimental paradigm to characterize the dynamics of defensive mobilization to body sensations increasing in intensity and aversiveness. Persons reporting low and high suffocation fear (SF; N = 69) were exposed to increasingly unpleasant feelings of dyspnea induced by inspiratory resistive loads and a breathing occlusion requiring voluntary breath holding. Respiratory responses were assessed along with subjective reports of anxiety and panic symptoms. Presentation of respiratory loads with increasing physical resistance led to increasingly unpleasant feelings of dyspnea. Twenty-eight participants terminated the exposure prematurely at least once. When dyspnea was severe, high compared to low SF persons exhibited an increased respiratory rate that was accompanied by reports of more intense panic symptoms. Premature terminations of exposure were preceded by a surge in anxiety, breathing frequency, and mouth pressure, and a decrease in tidal volume. We successfully established an experimental paradigm to assess changes in defensive responding with increasing intensity of an interoceptive threat. The current data foster our understanding of behavioral expression patterns observed in patients with anxiety and/or respiratory diseases and the processes involved in the culmination of bodily sensations and anxiety into panic.