PANIK-Netz: Subproject P7

Emotional processing and the fear circuit in the course of CBT intervention: a multicentre 3 Tesla FMRI study in panic disorder

Principal Investigator
Univ.-Prof. Dr. Tilo Kircher
Department of Psychiatry and Psychotherapy
RWTH Aachen University
Pauwelsstrasse 30
52074 Aachen
Tel. 0241/8089637
Fax. 0241/8082401

Duration applied for
3 years

Project Description
Introduction/state of the art
It has been hypothesized that patients with panic disorder (PD) inherit a particularly sensitive central nervous fear mechanism (Barlow 1997). The main structures known to be involved are the central nucleus of the amygdala, the hippocampus, thalamus, hypothalamus, periaqueductal grey and locus coeruleus, while potential cortical components remain less clear (Gorman et al. 2000). Potentially, abnormal processing in these “fear network” pathways could result in the misinterpretation of cues that are a key clinical feature of panic disorder. Cognitive behavioral therapy (CBT) most likely operates on a more conscious, cortical level, reducing phobic avoidance by deconditioning contextual fear and/or changing the pathophysiology of habituation processes. Fear conditioning studies have shown that information on threat-related sensory input can reach the amygdala via a fast subcorticalamygdala route as well as a slower thalamocortical-amygdala pathway. Amygdala responses may be probed with masked and unmasked face stimuli during fMRI conveying fearfulness in a conscious and unconscious manner, which is modulated by anxiety state in healthy subjects (Etkin et al. 2004). No such studies are available in panic disorder patients, and treatment effects have not been examined. Previous FMRI studies have often been hampered by the small numbers of participants, with the inherent selection bias and statistical inference problems. Further, modulating or causal influences (e.g. genetic, psychopathology, life events) within patients of one diagnostic group cannot be analysed due to small numbers. Therefore, first multicentre fMRI studies have been conducted. An own such study in schizophrenia has been performed including 80 patients and 80 controls from 9 centres. We could demonstrate the feasibility and advantages of such a multicentre approach (Stöcker et al 2005, Schneider et al in press) and will apply this expertise to panic disorder in the current application. Exploration of the neural networks underlying panic disorder to obtain potential prognostic data in conjunction with treatment effects will provide an important step towards a better understanding of its pathophysiology and thus open new options for improved treatments.

Using fMRI we want to evaluate putative neurobiological foundations of the psychotherapeutic process in panic disorder during two types of therapy (CbT vs cBT). This will be assessed by performing all fMRI examinations as a pre/post treatment design. Furthermore, one paradigm will be devoted to explicitly test the cerebral functioning of conditioning and habituation and/or extinction processes. As a complementary approach, processing of exteroceptive and enteroceptive threat cues designed to be salient for PD patients will be studied with the twofold goal of measuring potential predictors of therapeutic outcome and to assess the possible change after successful treatment in the cerebral processing of such material. The exteroceptive stimuli will be based on the established picture paradigms by Pauli, the enteroceptive processing will be based on monitoring heart tones of different rate and subjective attribution (in development in Münster based on Critchley et al. 2004) The general methodological strength lies in applying paradigms of core relevance for PD in a multicenter study using solely 3T scanners. Reassessments after therapy aim to probe the neural correlates of differential therapeutic effects related to clinical outcome. The advantages of 3 T compared to 1.5 T measurements are based on the increased signal-to-noise ratio, which can be exploited in the cortex and also in subcortical regions such as the amygdala using special sequence and processing developments (e.g., Robinson et al 2004, Habel et al submitted). Attending to necessarily required quality assurance of scanner and stimulation hardware we want to focus on the following questions: 

1. Which brain areas and in particular which components of the “fear circuit” are
differentially involved in the different clinical characteristics of panic disorder?

2. Which components of the neural circuit involved can be modulated by CBT treatment?

3. Do specific brain activation patterns before CBT treatment predict outcome?

Own previous work
Since 1999, the Aachen/Jülich psychiatric neuroimaging group has been leading the multicenter fMRI study “Functional Cerebral Indicators of Relapse”, a subproject of the German Competence Network on Schizophrenia financed by the BMBF. Spanning 9 centres, 80 firstepisode schizophrenia patients and 80 matched healthy controls have been investigated (Schneider et al, in press). Therefore a fully automated quality assurance routine for fMRI data was developed in this previous project (Stöcker et al, 2005). The developed strategies enable us to include and pool data of excellent quality, demonstrating the feasibility and advantages of mulitcenter fMRI studies. Conditioning paradigms have been studied in patients with the anxiety disorder social phobia (Schneider et al. 1999). The Münster site has longstanding expertise in brain imaging of patients with PD. AE worked several years as an investigator for the NIMH funded Center for Neural Systems of Fear and Anxiety at Cornell University in New York, where brain imaging paradigms to probe processing of anticipatory threat and salient anxiety-provoking materials for PD were developed and employed. At Münster up to now a total of 40 patients with panic disorder and 40 controls have been investigated using paradigms probing exterozeption (neutral sounds, Ekman and Friesen faces). In the first imaging genomics study in PD a significant influence of the serotonin 1A receptor genotype on fear circuits in PD was demonstrated (Domschke et al., in press). The Berlin group has been instrumental in establishing this imaging genomics approach for the fear network (Heinz et al. 2005). All participating neuroimaging centers (Aachen, Münster, Berlin) and their respective P.I.’s thus have long-standing experience in performing functional neuroimaging studies in psychiatric patients. Multiple own studies and publications have demonstrated the excellence of the P.I.’s . Technical equipment (3 T scanners, computers, software, work places, etc.) and overhead will be supplied free of charge in all sites.

Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J, Hohoff C, Kersting A, Engelien A, Arolt V, Heindel W, Deckert J. Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal and amygdale activation measured with 3T fMRI in panic disorder. International Journal of Neuropsychopharmacology in press, 2005, doi: 10.1017/S1461145705005869.

Heinz A, Braus D.F., Smolka MN, Wrase J, Hermann D, Klein S, Grüsser SM, Flor H, Schumann G, Mann K, Büchel C: Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature Neuroscience 8: 20-21, 2005.

Kircher TT, Liddle PF, Brammer MJ, Williams SCR, Murray RM, McGuire PK. Neural correlates of formal thought disorder in schizophrenia. Archives of General Psychiatry 58: 769-774, 2001.

Schneider F, Habel H, Klein M, Kellermann T, Stoecker T, Shah NJ, Zilles K, Braus DF, Schmitt A, Schlösser R, Wagner M, Frommann I, Kircher T, Rapp A, Meisenzahl E, Ufer S, Ruhrmann S, Thienel R, Sauer H, Henn FA, Gaebel W. A multi-center fMRI study of cognitive dysfunction in first-episode schizophrenia patients. Schizophrenia Research in press, 2005.

Schneider F, Weiss U, Kessler C, Müller-Gärtner H-W, Posse S, Grodd W, Flor H, Gaebel W, Birbaumer N. Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia. Biological Psychiatry 45: 863-871, 1999.

Stöcker T, Schneider F, Klein M, Habel U, Kellermann T, Zilles K, Shah NJ. Automated quality assurance routines for fMRI data applied to a multi-center study. Human Brain Mapping 25:237-246, 2005

Work Program
We are going to investigate 60 patients with panic disorder and 60 healthy control subjects twice using fMRI pre and post CBT treatment at 3 centers. Patients from the waiting list will serve as further controls in accordance with the core therapy outcome project. All consenting patients will be selected from the larger core clinical therapy sample (n>180 at the 3 centers). Following an initial fMRI scan, patients will undergo either therapist guided exposure (cBT; n=20), cognitive focused therapy (CbT; n=20) or WLC (n=20). Following a period of 7 weeks therapy patients or patients after the waiting list period and healthy control subjects will be reexamined. We assume a participation rate of 30% of all patients, a drop out rate of consenting patients of 10 % and 10% data loss due to poor quality (conservative estimates based on multicenter study, “Competence Network on Schizophrenia” coordinated by Aachen and two studies with panic disorder patients at Münster with a participation rate of 60% and a drop out rate of 5%). To obtain large enough numbers therefore in all participating centers all paradigms will be carried out:

1) Exteroception of fear related stimuli. This paradigm will focus on the conscious perception of panic-relevant, anxiety-relevant but panic irrelevant and neutral pictures, utilizing images from previous EEG work of members of our network (Wiedemann et al. 1999). Stimuli will be presented each for 4 sec, followed by an interval of .5 sec. There will be an implicit yes/no task, e.g. “Are there more than three persons in the picture?”. The paradigm will be performed as a robust block design. We expect strongest signal changes in the amygdale in the PD patients for the panic-relevant vs. anxiety-relevant pictures before vs. after therapy. We further expect stronger changes in the cBT vs. the CbT group.

2) Enteroception of fear related stimuli. Here we will focus on misinterpretation of sensory information, i.e. bodily cues, known to be a hallmark of panic disorder and their cognitive attribution, a paradigm currently implemented at Münster (Critchley et al. 2004). Subjects’ will be told, that their heart rate will be measured by ECG in the scanner. Tones in the frequency of ICU continuous ECG will be played to the subjects, which however will be unrelated to the actual heart rate. The two factors “frequency” (fast vs. slow beats) and “feedback” (“subject’s heart rate” vs. “unrelated tones”) will be varied systematically. The task will be to attend to the tones. The paradigm will be performed as a block design. We expect strongest signal changes in the amygdale in the PD patients for the fast subject’s heart rate condition before vs. after therapy. We further expect stronger changes in the cBT vs. the CbT group.

3) Conditioning and habituation. The differential responses to conditioning and extinction of not-panic related stimuli will be investigated. Neutral visual stimuli will be associated with white noise as unconditioned stimulus (UCS) in an aversive differential classical conditioning paradigm (Buchel et al. 1998). Subjects will perform the usual three experimental phases of learning. During habituation two neutral but socially and ecologically relevant visual stimuli (neutral faces) will be presented repeatedly (30 times). These stimuli will later serve as CS+ and CS-. Furthermore, the white noise serving as unconditioned stimulus will also be presented 30 times. Presentation of all stimuli will be randomized and fMRI measurements will apply an event-related design. During acquisition one neutral face (CS+) will be paired with the aversive unconditioned stimulus, the white noise, while the other remains without consequences (CS-). 60 pairings (30 CS+, 30 CS-) will be performed as well as a partial reinforcement strategy in which only 50 % of CS+ pairings are paired with the US. This guarantees learning and stimulus-response associations and enables at the same time the analysis of BOLD responses to the CS+ in the absence of the US with the advantage of avoiding confounding effects of the associated aversive tone. Data analyses will hence compare the response to the CS+ (not paired with US) to the CS-. During extinction only the CS will be presented (each CS for 30 times) without any US pairing and the course of habituation of learned responses will be assessed. This paradigm will be carried out in an event related design. We hypothesise that patients with panic disorder demonstrate faster conditioning and slowerextinction. Patients will exhibit a hyperreaction during acquisition especially in the amygdala, causing hyperactivation also in the associated networks as well as a slower habituation and/or a prolonged response in the amygdala during extinction compared to healthy controls. We further expect no differences in activation in the amygdale and other areas of a subcorticalcortical fear network, i.e. the orbitofrontal cortex and the thalamus in the the CbT vs. control group after therapy.

All paradigms will be set up within three months and will first be evaluated in a pilot study with healthy controls in all centres in the next three months and thus will be available at the beginning of the clinical trial. Standardized fMRI and MP-Rage parameters will be used in all centres. All fMRI procedures will not take longer than 45 min together to guarantee optimal compliance. Quality control of scanner and stimulation hardware will be performed according to the routines developed in the previous multicentre fMRI study (Stöcker et al 2005). All fMRI scans will be accompanied by simultaneous recording of autonomic measures, in particular heart rate and skin conductance which will be measured prior to the measurement, during the measurement and after the measurement in parallel to interviews evaluating the state of anxiety allowing for subjective and objective measurements of anticipatory anxiety, anxiety during measurement and anxiety after recovery/baseline. This design will thus allow not only to evaluate the role of various brain regions for panic disorder, their modulation by CBT and their relevance for therapeutic outcome, but also a correlation with some of the psychophysiological intermediate phenotypes.

Cooperation and add-on
The study will be performed within the core clinical trial (P2). Members of participating centers will meet every 3 months to discuss and solve problems. To correlate findings with those of the psychophysiological and neuroendocrinological investigations (P4, P5), measurements will be performed at the identical time point during the clinical trial and psychophysiological measurements (heart rate, skin conductance) as well as an anticipation paradigm will also be employed. At Münster, all patients undergoing the fMRI measurement will also undergo the psychophysiological protocol by Dr. Gerlach, Münster (P5b). Genotyping in all participants will be performed in cooperation with the project of Prof Deckert, Münster (P6).

Ethical and legal considerations
The main consideration of this research is the protection of private data. This will be ensured by an anonymization procedure. No serious adverse events will be expected during fMRI measurements. Ethical votes and written informed consent will be obtained according to the Helsinki principles.