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Emotional-associative learning processes such as fear conditioning and extinction are highly relevant to not only the development and maintenance of anxiety disorders (ADs), but also to their treatment. Extinction, as the laboratory analogue to behavioral exposure, is assumed a core process underlying the treatment of ADs. Although exposure-based treatments are highly effective for the average patient suffering from an AD, there remains a gap in treatment efficacy with over one third of patients failing to achieve clinically significant symptom relief. There is ergo a pressing need for intensified research regarding the underlying neural mechanisms of aberrant emotional-associative learning processes and the neurobiological moderators of treatment (non-)response in ADs.
The current thesis focuses on different applications of the fundamental principles of fear conditioning and extinction by using two example cases of ADs from two different multicenter trials. First, we targeted alterations in fear acquisition, extinction, and its recall as a function of psychopathology in panic disorder (PD) patients compared to healthy subjects using fMRI. Second, exposure-based therapy and pre-treatment patient characteristics exerting a moderating influence on this essential learning process later on (i.e. treatment outcome) were examined using multimodal functional and structural neuroimaging in spider phobia.
We observed aberrations in emotional-associative learning processes in PD patients compared to healthy subjects indicated by an accelerated fear acquisition and an attenuated extinction recall. Furthermore, pre-treatment differences related to defensive, regulatory, attentional, and perceptual processes may exert a moderating influence on treatment outcome to behavioral exposure in spider phobia. Although the current results need further replication, on an integrative meta level, results point to a hyperactive defensive network system and deficient emotion regulation processes (including extinction processes) and top-down control in ADs. This speaks in favor of transdiagnostic deficits in important functional domains in ADs.
Deficits in transdiagnostic domains such as emotion regulation processes could be targeted by enhancing extinction learning or by means of promising tools like neurofeedback. The detection of pre-treatment clinical response moderators, for instance via machine learning frameworks, may help in supporting clinical decision making on individually tailored treatment approaches or, respectively, to avoid ineffective treatment and its related financial costs. In the long run, the identification of neurobiological markers which are capable of detecting non-responders a priori represents an ultimate goal.
Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.
Angststörungen gehören zu den häufigsten psychischen Erkrankungen in Deutschland, dabei könnten Hirnstimulationstechniken unterstützend zu bisherigen Therapieverfahren Anwendung finden. Für die Entstehung und Behandlung von Angststörungen spielen die Prozesse der Konditionierung und Extinktion eine große Rolle, wobei im präfrontalen Kortex eine erhöhte Aktivität gemessen werden kann. 51 gesunde Probanden nahmen an einem Furchtkonditionierungsexperiment mit zwei männlichen Gesichtern als CS+ und CS- sowie einem Schrei als aversiven Stimulus teil. Es wurde untersucht, inwieweit die bilaterale transkranielle Gleichstromstimulation (tDCS) des dorsolateralen präfrontalen Kortex die Extinktion moduliert. Die Stimulation erfolgte mittels tDCS links-kathodal über Position F3, rechts-anodal über Position F4 für 20 Minuten mit 2 mA und einer Elektrodengröße von 35 cm². Es wurden die Hautleitfähigkeit und der Startle-Reflex als physiologische Parameter der Furcht erfasst sowie Valenz und Arousal für die Stimuli durch subjektive Ratings erhoben. Bei den erfolgreich konditionierten Probanden (n = 28) kam es in der verum-tDCS-Gruppe während der frühen Extinktion zu einer signifikanten Zunahme der Hautleitfähigkeit auf CS-. Möglicherweise wurde durch die tDCS-Stimulation des dorsolateralen präfrontalen Kortex eine Furchtgeneralisierung ausgelöst. Ein anderer Erklärungsansatz für die gefundenen Ergebnisse ist die Modulation von Aufmerksamkeitsprozessen durch die Stimulation. Weitere Forschung ist nötig, bevor eine klinische tDCS-Anwendung bei Patienten mit Angststörungen möglich ist.
Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.