PANIK-Netz: Subproject P5

Psychophysiological and endocrinological correlates of CBT treatment effects in panic disorder: Overarching multicenter-project

Prof. Dr. Alfons Hamm
Institut für Psychologie
Franz-Mehring-Str. 47
17487 Greifswald
Tel: +49(0)3834 863716
Fax: +49(0)3834 863763

Duration applied for
3 years

Project Description
Introduction/state of the art
Modern learning theories assume that initial panic attacks set the stage for development of panic disorder and its three elements, recurrent panic attacks, anticipatory anxiety, and agoraphobic avoidance (Bouton, Mineka, & Barlow, 2001). Following an initial panic attack, anticipatory anxiety is associated with diverse internal (heart racing, drowsiness) and external (crowds, heat) cues that in turn induce an increase in anxious arousal. Increased anticipatory anxiety, which is characterized as a state of heightened emotional and physiological arousal accompanied by hypervigilance towards potentially dangerous stimuli, comprises an increased chance of experiencing another attack and also motivates agoraphobic avoidance. This state of anxious apprehension can be assessed by various psychophysiological measures such as increase in heart rate, blood pressure, respiration, and sweat gland activity. While such autonomic measures are well suited to assess the intensity of emotional arousal, recent evidence suggests that the modulation of the startle response (a fast protective reflex to a sudden acoustic stimulus) specifically indexes the activation of the defense or fear system of an organism. Accumulating evidence both from animal and human experimentation suggests that the amygdala, a limbic structure located in the anterior temporal lobe is the core structure involved in the regulation of the defense system of an organism. Human studies using modern brain imaging techniques have confirmed animal data in that anticipatory anxiety may be associated with increased activation of the left amygdala, left insula and the anterior cingulated cortex (Monk et al., 2003; Phelps et al., 2001). The potentiation of the startle reflex is modulated by the same neural circuits. It has been shown in animals that the startle reflex is reliably potentiated after amygdala stimulation, and completely blocked after bilateral lesions of the amygdala (Davis, 2000). Accordingly, clear impairment of fear potentiated startle has been demonstrated in humans after unilateral amygdala lesions in (Weike et al., 2005). Therefore by measuring startle modulation and autonomic responses during anticipatory anxiety in panic disorder patients the current projects are an important linkage and extension of the fMRI projects in the current research proposal. The overarching project (P5) will investigate the effects of CBT on autonomic responding (emotional intensity) and startle reactivity (as an index of the activation of the subcortical defense system) during anxious apprehension.

Cognitive behavioral treatment of PD/AG aims to reduce anticipatory anxiety and reduce or eliminate panic responses. By using exposure based and cognitive interventions the major aim is to enable the patient to gather new learning experiences that reduce anticipatory anxiety and agoraphobic avoidance. Although these cognitive behavioral treatments have been shown to be overall effective if carried out properly, it is still completely unclear how these treatments affect the neural circuitry in the brain and whether this is related to systematic changes in verbal report, autonomic arousal, and startle reactivity. Most clinical studies testing the efficacy of CBT in treating panic disorder heavily rely on verbal reports of symptom frequency and severity as assessed by several self report measures. These self reports are often biased by intentions of self-representation or by specific situational demands. Therefore, the measurement of autonomic arousal will add an important aspect in evaluating the treatment effects of CBT. On the other hand, autonomic measures (like blood pressure, heart rate or skin conductance) are primarily linked to the intensity of affective stimulation and might therefore index only one part of the effects of CBT. In contrast, startle modulation operates on a very fundamental level outside of subject’s awareness and is mediated by the activation of the subcortical fear network. The current overarching project will assess for the first time, whether CBT will be able to change the fear networks on this basic subcortical level. Moreover it will be investigated which elements of the treatment will change the intensity of the affect (probably due to habituation) and which ingredients are important to change the subcortical fear system. More importantly, it is not known, which elements of CBT are essential (therapist guided or self guided exposure or cognitive reframing) for long-term changes in the fear/anxiety network outlined above. The current project is aimed at investigating which psychophysiological and endocrinological changes specifically correlate with treatment effects of cognitive behaviour therapy.

Own previous work and resources of the overarching project
All three centers (Greifswald, Münster, Würzburg) that participate in the overarching project have extensive experience in the psychophysiological research of anxiety disorders. This expertise comprises the sophisticated experience in measuring various autonomic responses and in implementing various experimental paradigms to induce anticipatory anxiety. Moreover, all three centers have experience in measuring startle modulation and are structured to do these measurements in a multicenter clinical trial. These expertises are documented by various publications which will be referred to in the description of the individual center projects.

Work program of the overarching project:
All three centers will assess the treatment effects of CBT on anxious apprehension using the measures described above. In the overarching project anxious apprehension will be induced by instructing all patients that after an anticipation period of 10 minutes they have to stay in a narrow dark room with the door locked as long as they can. It has been shown in a number of studies that confining anxiety patients in a narrow compartment for several minutes will often induce typical panic symptoms (palpitations, short of breath, dizziness etc.). Autonomic arousal and startle modulation during anticipation and exposure to this standardized situation will be assessed. Moreover, the duration they can stay in the compartment will be used as a measure for behavioral avoidance. This psychophysiological assessment will be conducted (a) at the beginning of CBT, (b) after the cognitive reframing phase, (c) after exposure treatment, (d) after therapy, and (e) a 6 months follow up. Moreover, it will be investigated whether treatment responders and non-responders can be differentiated by these psychophysiological correlates, and how these psychophysiological response patterns relate to changes in neural activation of the fear circuit as assessed in the brain imaging studies (see P7). Patients will be recruited in the Psychotherapy Outpatient Clinics at the Universities of Greifswald, Muenster, and Wuerzburg. 60 Patients will be studied in each center resulting in overall 180 participants. Patients will undergo the same treatment procedures as in the core clinical network.

Cooperation and Add-on
The multicenter study will for the first time investigate how CBT will change psychophysiological responding during anticipatory anxiety. The relative large sample will enable us to differentiate between responders and non-responders. Moreover, we will be able to relate the treatment response obtained in the verbal report data not only to behavioral but also to physiological data. We will also be able to relate the psychophysiological responses to brain imaging data of the fMRI group. We also will be able to differentiate the psychophysiological response patterns elicited by the anticipation of different challenges to induce aversive internal cues. This might also help to differentiate between different types of panic disorders. Finally we will be able to relate clinical data (various outcome measures) to physiological response patterns, hemodynamic patterns in the brain, and last not least to changes in the endocrine system. In a first step we will establish the basic laboratory assessment. To organize this methodological exchange we will have several meetings of the PIs of the groups in Greifswald, Muenster, and Wuerzburg. The meetings will take place on each Friday every two weeks in Muenster and will be organized as a lab meeting. As soon as the assessment procedure is established, the psychophysiology group will have regular meetings each first Friday within two months. For establishing the proper collection of the saliva samples, the PIs of the three groups in Greifswald, Muenster, and Wuerzburg will participate in a methodological workshop in Dresden. The first few saliva samples will be sent to Dresden, to see whether the samples were correctly collected and can be analyzed properly. The Dresden group will join the bimonthly lab meetings as soon as some cortisol data are available. Finally the group will present the findings of this multicenter study at international meetings. We plan to organize a symposium on the 47th Meeting of the Society for Psychophysiological Research in Savannah 2007. We also plan to organize a symposium on the next APM meeting 2007 in Germany, which will probably take place in Greifswald. 

Ethical and legal considerations
No unusual risks or ethical concerns involved.