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

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

Effects of Cognitive Behavioral Therapy on Neural Processing of Agoraphobia-Specific Stimuli in Panic Disorder and Agoraphobia.

BACKGROUND: Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. METHODS: We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. RESULTS: A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. CONCLUSIONS: For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.

Patients' characteristics and their influence on course of fear during agoraphobic symptom provocation: may SS(N)RI treatment compensate unfavorable individual preconditions?

BACKGROUND: Patients' characteristics and antidepressants are discussed to be relevant in the context of phobic exposure. AIMS: To identify patients characteristics associated with a differential course of fear during disorder-specific symptom provocation as well as to elucidate the effect of selective serotonin-(noradrenalin-) reuptake inhibitors [SS(N)RI] on development of fear in the context of re-exposure to the phobic stimuli. METHODS: Twenty-eight clinically well-characterized patients with panic disorder and agoraphobia (PD/AG) were classified into subjects who show a reduction of fear ('Fear-') during a symptom provocation via a picture-based paradigm (T1) and those who did not ('Fear+'). Subsequently, SS(N)RI treatment was administered to all patients and subjects were re-exposed to the feared stimuli after 8 weeks of treatment (T2). Moreover, brain activity within the 'fear network' was measured via functional magnetic resonance imaging (fMRI) at T1 and T2. RESULTS: Fear - were significantly younger and demonstrated increased exposure-related fear as well as stronger activity in several fear-related brain areas than Fear+. We found significant improvements in all clinical parameters after pharmacological intervention for the whole sample (T1-T2; all measures p < .02). However, reduction of fear as well as activation in (para)limbic structures during symptom provocation were now attenuated in Fear - but increased in Fear+. CONCLUSIONS: Advanced age may predict a therapeutically unfavorable course of fear during agoraphobic symptom provocation. Since we found no negative impact of medication on fear development at all, there was some evidence that SS(N)RI treatment might improve the individual ability to get involved with the agoraphobic stimuli while conducting disorder-specific exposure.

Facing the fear--clinical and neural effects of cognitive behavioural and pharmacotherapy in panic disorder with agoraphobia.

INTRODUCTION: Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates. EXPERIMENTAL PROCEDURES: We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29). RESULTS: Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups. DISCUSSION: This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala's involvement in the fear system's sensitivity to treatment.

Event-related brain potentials and the efficiency of visual search for vertically and horizontally oriented stimuli.

Reports that visual search is more efficient for vertically than for horizontally shaded objects suggested that search is influenced by a priori knowledge about the source of light. In this study, we examined search for targets defined by the orientation of luminance gradients and measured event-related brain potentials (ERPs). In Experiment 1, we examined search for stimuli that comprised gradual luminance differences. Response times showed the expected orientation anisotropy effect. ERP amplitudes in the P1 latency range were slightly more positive in response to horizontally oriented stimuli, whereas P3 amplitudes were more positive in response to nonsingleton vertically oriented stimuli. Experiment 2 compared search for stimuli that comprised gradual versus step differences in luminance. All the anisotropies that we observed in Experiment 1 could be replicated in Experiment 2. Moreover, these anisotropies were not dependent on the type of the luminance gradient. This finding is inconsistent with the view that search efficiency is influenced by a priori knowledge about the source of light. The behavioral and electrophysiological data are consistent with a context model of visual search. We propose that contextual modulation reduces redundancy and contributes to computing the saliency of visual information by implementing divisive normalization and multiplicative filtering.