Alexander L. Gerlach

Interoceptive sensitivity in anxiety and anxiety disorders: An overview and integration of neurobiological findings

Interoceptive sensitivity, particularly regarding heartbeat, has been suggested to play a pivotal role in the pathogenesis of anxiety and anxiety disorders. This review provides an overview of methods which are frequently used to assess heartbeat perception in clinical studies and summarizes presently available results referring to interoceptive sensitivity with respect to heartbeat in anxiety-related traits (anxiety sensitivity, state/trait anxiety), panic disorder and other anxiety disorders. In addition, recent neurobiological studies of neuronal activation correlates of heartbeat perception using positron emission tomography (PET), functional magnetic resonance imaging (fMRI) or electroencephalographic (EEG) techniques are presented. Finally, possible clinical and therapeutic implications (e.g., beta-blockers, biofeedback therapy, cognitive interventions and interoceptive exposure) of the effects of heartbeat perception on anxiety and the anxiety disorders and the potential use of interoceptive sensitivity as an intermediate phenotype of anxiety disorders in future neurobiological and genetic studies are discussed.

Neuropeptide S receptor gene—converging evidence for a role in panic disorder

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn107Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case–control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Slow recovery from voluntary hyperventilation in panic disorder

Objective Because hyperventilation has figured prominently in theories of panic disorder (PD) but not of social phobia (SP), we compared predictions regarding diagnosis-specific differences in psychological and physiological measures before, during, and after voluntary hyperventilation. Method Physiological responses were recorded in 14 patients with PD, 24 patients with SP, and 24 controls during six cycles of 1-minute of fast breathing alternating with 1 minute of recovery, followed by 3 minutes of fast breathing and 10 minutes of recovery. Speed of fast breathing was paced by a tone modulated at 18 cycles/minute, and depth by feedback aimed at achieving an end-tidal pCO2 of 20 mm Hg. These values were reached equally by all groups. Results During fast breathing, PD and SP patients reported more anxiety than controls, and their feelings of dyspnea and suffocation increased more from baseline. Skin conductance declined more slowly in PD over the six 1-minute fast breathing periods. At the end of the final 10-minute recovery, PD patients reported more awareness of breathing, dyspnea, and fear of being short of breath, and their pCO2s, heart rates, and skin conductance levels had returned less toward normal levels than in other groups. Their lower pCO2s were associated with a higher frequency of sigh breaths. Conclusions PD and SP patients report more distress than controls to equal amounts of hypocapnia, but PD differ from SP patients and controls in having slower symptomatic and physiological recovery. This finding was not specifically predicted by hyperventilation, cognitive-behavioral, or suffocation alarm theories of PD.

Blushing and physiological arousability in social phobia

Blushing is the most prominent symptom of social phobia, and fear perception of visible anxiety symptoms is an important component of cognitive behavioral models of social phobia. However, it is not clear how physiological and psychological aspects of blushing and other somatic symptoms are linked in this disorder. The authors tested whether social situations trigger different facial blood volume changes (blushing) between social phobic persons with and without primary complaint of blushing and control participants. Thirty social phobic persons. 15 of whom were especially concerned about blushing, and 14 control participants were assessed while watching an embarrassing videotape, holding a conversation, and giving a talk. Only when watching the video did the social phobic persons blush more than controls blushed. Social phobic persons who complained of blushing did not blush more intensely than did social phobic persons without blushing complaints but had higher heart rates, possibly reflecting higher arousability of this subgroup.

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

Heartbeat perception in social anxiety before and during speech anticipation

According to current cognitive models of social phobia, individuals with social anxiety create a distorted image of themselves in social situations, relying, at least partially, on interoceptive cues. We investigated differences in heartbeat perception as a proxy of interoception in 48 individuals high and low in social anxiety at baseline and while anticipating a public speech. Results revealed lower error scores for high fearful participants both at baseline and during speech anticipation. Speech anticipation improved heartbeat perception in both groups only marginally. Eight of nine accurate perceivers as determined using a criterion of maximum difference between actual and counted beats were high socially anxious. Higher interoceptive accuracy might increase the risk of misinterpreting physical symptoms as visible signs of anxiety which then trigger negative evaluation by others. Treatment should take into account that in socially anxious individuals perceived physical arousal is likely to be accurate rather than false alarm.

Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia

Cognitive behavioral therapy (CBT) is efficacious for panic disorder with agoraphobia (PD/A). Nevertheless, the active ingredients of treatment and the mechanisms through which CBT achieves its effects remain largely unknown. The mechanisms of action in CBT (MAC) study was established to investigate these questions in 369 patients diagnosed with PD/A. The MAC study utilized a multi-center, randomized controlled design, with two active treatment conditions in which the administration of exposure was varied, and a wait-list control group. The special feature of MAC is the way in which imbedded experimental, psychophysiological, and neurobiological paradigms were included to elucidate therapeutic and psychopathological processes. This paper describes the aims and goals of the MAC study and the methods utilized to achieve them. All aspects of the research design (e.g., assessments, treatment, experimental procedures) were implemented so as to facilitate the detection of active therapeutic components, and the mediators and moderators of therapeutic change. To this end, clinical, behavioral, physiological, experimental, and genetic data were collected and will be integrated.

Studies on a German (Münster) version of the temperament auto-questionnaire TEMPS-A: construction and validation of the briefTEMPS-M

BACKGROUND Based on classic German concepts of a continuum between depressive, hyperthymic, cyclothymic, and irritable temperaments and affective disorder (and adding an anxious type to the four), Akiskal and co-workers developed the Temperament Evaluation of Memphis, Pisa, Paris and San Diego both in interview (TEMPS-I) and auto-questionnaire (TEMPS-A) versions. It is the aim of the present analyses to validate a brief German version of TEMPS-A. METHODS A total of 1056 students of the Westfalische-Wilhelms-Universitat in Munster, Germany, filled out the long 110-item version of the TEMPS-A (Munster translation by Erfurth: TEMPS-M) modified into a five gradation Likert format and with the items randomized. Based on this data we constructed a brief version of the TEMPS-M. In a second study, a sample of 151 students were recruited who filled out the briefTEMPS-M twice, approximately 1 month apart. RESULTS Our psychometric procedures resulted in the retention of 35 items from the original 110. The proposed five-factor structure of the original TEMPS-A was upheld, with relatively few item reclassification (mainly due to some overlap between depressive and anxious traits). Internal consistency (Cronbach alpha values ranging from 0.69 to 0.84) and test-retest reliability were shown. Most importantly, all temperaments in the briefTEMPS-M correlated quite well (Pearson r values ranging from 0.49 to 0.72) with their respective original versions in the longer TEMPS-M. As for construct validity, significant correlation was shown with the Beck Depression Inventory for all but the hyperthymic temperament; the hyperthymic, cyclothymic and irritable correlated highest with the self-report Manic Inventory. LIMITATIONS The study sample of university students was selective. CONCLUSIONS We were able to construct a brief German version of the TEMPS-A auto-questionnaire. We submit this shorter version will be suitable for both clinical (psychiatric and general medical) and neurobiological research, as well as in studies on temperament features in selected populations, e.g., allowing comparisons between regions or different (German-speaking) countries.

Embarrassment and social phobia: the role of parasympathetic activation

The few studies on the psychophysiology of embarrassment have suggested involvement of parasympathetic activation. However, blushing, the hallmark of embarrassment and a prominent symptom in social phobia, is more likely to be produced by cervical sympathetic outflow. Hitherto, there has been no evidence of parasympathetic innervation of the facial blood vessels. In this study, a group of social phobics and control participants watched, together with a 2-person audience, a previously made videotape of themselves singing a childrens song. Self-report measures confirmed that this task induced embarrassment. While two measures of respiratory sinus arrhythmia (RSA) during the task did not indicate heightened parasympathetic tone, increased heart rate (HR) and skin conductance marked sympathetic activation. Thus, our data do not support the notion that an increase in parasympathetic activation plays a significant role in social phobia and embarrassment. Social anxiety and embarrassment both resulted in sympathetic activation.

Influence of alcohol on the processing of emotional facial expressions in individuals with social phobia

OBJECTIVES Individuals with social phobia are at an increased risk to develop alcohol problems. However, the mechanism responsible for this association is unclear. It has been suggested that alcohol reduces anxiety by impairing initial appraisal of threatening stimuli. Information that is especially threatening, however, may be resistant to such an effect of alcohol. We tested the influence of alcohol on the appraisal of five emotional facial expressions. METHODS 40 social phobia patients and 40 controls performed a dot probe task, after drinking either alcohol or orange juice. Stimuli were faces with happy, angry, neutral and also two ambiguous expressions that were formed by blending angry or happy faces and neutral faces. Stimuli were presented for either 175 or 600 ms. RESULT Sober patients showed an attentional bias towards angry faces, indicating preferential processing of threat stimuli. Alcohol significantly reduced this bias. Only in sober participants, this attentional bias correlated with measures of social anxiety. In controls, no biases were observed. CONCLUSIONS Alcohol seems to attenuate the impact of threatening social stimuli on social phobia patients, which may negatively reinforce the consumption of alcohol and at least partially explain the heightened comorbidity with alcohol related problems known from epidemiological studies. The dot probe task with short stimulus presentation times seems to provide an adequate method to demonstrate alcohol effects on information processing.