Thomas Straube

Waiting for spiders: Brain activation during anticipatory anxiety in spider phobics

Anticipatory anxiety during expectation of phobogenic stimuli is an integral part of abnormal behaviour in phobics. The neural basis of anticipatory anxiety in specific phobia is unknown. Using functional magnetic resonance imaging (fMRI), we explored brain activation in subjects with spider phobia and in non-phobic subjects, while participants anticipated the presentation of either neutral or phobogenic visual stimuli. Subjective ratings indicated that anticipation of phobia-related stimuli was associated with increased anxiety in phobics but not in healthy subjects. FMRI results showed increased activation of the dorsal anterior cingulate cortex (ACC), insula, thalamus, and visual areas in phobics compared to controls during anticipation of phobia-relevant versus anticipation of neutral stimulation. Furthermore, for this contrast, we found also increased activation of the bed nucleus of the stria terminalis (BNST). This particular finding supports models, which propose, based on animal experiments, a critical involvement of the BNST in anticipatory anxiety. Finally, correlation analysis revealed that subjective anxiety of phobics correlated significantly with activation in rostral and dorsal ACC and the anterior medial prefrontal cortex. Thus, activation in different ACC regions and the medial prefrontal cortex seems to be specifically associated with the severity of experienced anticipatory anxiety in subjects with spider phobia.

Effects of cognitive-behavioral therapy on brain activation in specific phobia

Little is known about the effects of successful psychotherapy on brain function in subjects with anxiety disorders. The present study aimed to identify changes in brain activation following cognitive-behavioral therapy (CBT) in subjects suffering from specific phobia. Using functional magnetic resonance imaging (fMRI), brain activation to spider videos was measured in 28 spider phobic and 14 healthy control subjects. Phobics were randomly assigned to a therapy-group (TG) and a waiting-list control group (WG). Both groups of phobics were scanned twice. Between scanning sessions, CBT was given to the TG. Before therapy, brain activation did not differ between both groups of phobics. As compared to control subjects, phobics showed greater responses to spider vs. control videos in the insula and anterior cingulate cortex (ACC). CBT strongly reduced phobic symptoms in the TG while the WG remained behaviorally unchanged. In the second scanning session, a significant reduction of hyperactivity in the insula and ACC was found in the TG compared to the WG. These results propose that increased activation in the insula and ACC is associated with specific phobia, whereas an attenuation of these brain responses correlates with successful therapeutic intervention.

Brain activation to phobia-related pictures in spider phobic humans: an event-related functional magnetic resonance imaging study

Using event-related functional magnetic resonance imaging we investigated blood oxygen level dependent brain activation in spider phobic and non-phobic subjects while exposed to phobia-related pictures (spiders) and non-phobia-related pictures (snakes and mushrooms). In contrast to previous studies, we show significantly increased amygdala activation in spider phobics, but not in controls, during presentation of phobia-relevant visual stimuli. Furthermore, phobia-specific increased activation was also found in the insula, the orbitofrontal cortex and the uncus. Our study confirms the role of the amygdala in fear processing and provides insights into brain activation patterns when animal phobics are confronted with phobia-related stimuli.

Common and distinct brain activation to threat and safety signals in social phobia

Background: Little is known about the functional neuroanatomy underlying the processing of emotional stimuli in social phobia. Objectives: To investigate specific brain activation that is associated with the processing of threat and safety signals in social phobics. Methods: Using functional magnetic resonance imaging, brain activation was measured in social phobic and nonphobic subjects during the presentation of angry, happy and neutral facial expressions under free viewing conditions. Results: Compared to controls, phobics showed increased activation of extrastriate visual cortex regardless of facial expression. Angry, but not neutral or happy, faces elicited greater insula responses in phobics. In contrast, both angry and happy faces led to increased amygdala activation in phobics. Conclusions: The results support the hypothesis that the amygdala is involved in the processing of negative and positive stimuli. Furthermore, social phobics respond sensitively not only to threatening but also to accepting faces and common and distinct neural mechanisms appear to be associated with the processing of threat versus safety signals.

Neural mechanisms of automatic and direct processing of phobogenic stimuli in specific phobia.

BACKGROUND The study aimed to identify brain activation during direct and automatic processing of phobogenic stimuli in specific phobia. METHODS Responses to phobia-related and neutral pictures (spiders and mushrooms) were measured by means of event-related functional magnetic resonance imaging during two different tasks. In the identification task, subjects were asked to identify the object (spider or mushroom). In a demanding distraction task, subjects had to match geometric figures displayed in the foreground of the pictures. RESULTS Phobics showed greater responses to spiders versus mushrooms in the left amygdala, left insula, left anterior cingulate gyrus (ACC), and left dorsomedial prefrontal cortex (DMPFC) during the identification task and in the left and right amygdala during the distraction task. All of these activations were also significantly increased compared to control subjects who did not show stronger brain activation to spiders versus mushrooms under any task condition. CONCLUSIONS Our findings propose specific neural correlates of automatic versus direct evaluation of phobia-relevant threat. While the amygdala, especially the right amygdala, seems to be crucially involved in automatic stimuli processing, activation of areas such as the insula, ACC and DMPFC is rather associated with direct threat evaluation and requires sufficient attentional resources.

Requirement of β-adrenergic receptor activation and protein synthesis for LTP-reinforcement by novelty in rat dentate gyrus

Long‐term potentiation (LTP) is supposed to be a cellular mechanism involved in memory formation. Similar to distinct types of memory formation, LTP can be separated into a protein synthesis‐independent early phase (early‐LTP) and a protein synthesis‐dependent late phase (late‐LTP). An important question is whether the transformation from early‐ into late‐LTP can be elicited by behavioural conditions such as the attention to novel events. Therefore, we investigated the effect of exploration of a novel environment (novelty‐exploration) on subsequently induced early‐LTP in the dentate gyrus of freely moving rats. While a delay of 60 min between exploration onset and LTP induction had no effect, intervals of 30 or 15 min led to a reinforcement of early‐ to late‐LTP. Exploration of a familiar environment failed to prolong LTP maintenance. The novelty‐induced LTP reinforcement was blocked when the translation inhibitor anisomycin or the β‐adrenergic antagonist propranolol were applied intracerebroventricularly before exploration onset. These findings support the hypothesis that the synergistic interplay of novelty‐triggered noradrenergic activity and weak tetanic stimulation promotes the synthesis of certain proteins that are required for late‐LTP. Such a cellular mechanism may underlie novelty‐dependent enhancement of memory formation.

A Single-Trial Estimation of the Feedback-Related Negativity and Its Relation to BOLD Responses in a Time-Estimation Task

An event-related potential (ERP) component reliably associated with feedback processing and well studied in humans is the feedback-related negativity (FRN), which is assumed to indicate activation of midcingulate cortex (MCC) neurons. However, recent approaches have conceptualized this frontocentral ERP component as reflecting at least partially a reward positivity associated with activation in reward-related brain regions, in line with fMRI studies investigating feedback processing in the context of reward evaluation. To discover convergence of electrophysiological and BOLD responses elicited by performance feedback, we concurrently recorded EEG and fMRI during a time-estimation task. The ERP showed relatively more negative amplitudes to negative than to positive feedback. Conventional analyses of fMRI data revealed activation of a number of areas, including ventral striatum, anterior cingulate cortex, and medial prefrontal cortex to positive versus negative feedback. Most importantly, when using single-trial amplitudes of electrophysiological feedback signals to estimate hemodynamic responses, we found feedback-related BOLD-responses in ventral striatum, midcingulate, and midfrontal cortices to positive but not to negative feedback associated with feedback signals in the time range of the FRN. Specifically, activation in these areas increased as amplitudes became more positive. These findings suggest that, in the time-estimation task, a positivity elicited by reward is associated with brain activation in several reward-related brain regions and is driving differential ERP responses in the time range of the FRN.

Bidirectional modulation of long-term potentiation by novelty-exploration in rat dentate gyrus

Previous studies have shown that exploration of a novel environment reverses hippocampal long-term potentiation (LTP). Here we demonstrate a bidirectional modulation of LTP measured in the dentate gyrus of freely moving rats by means of novelty exploration. A transient form of LTP lasting about 6 h was induced in perforant path-granular cell-synapses by a weak tetanization protocol (three bursts of 15 pulses at f=200 Hz). LTP was reversed when non-restricted exploration of a novel environment started 2 min after LTP induction. In contrast, using the same interval and limiting the exploration duration to 1 min led to LTP-prolongation. Furthermore, LTP-reinforcement was also obtained when a not-restricted exploration started within 2 min before tetanization. The observed interplay of LTP-impairing and -enhancing factors may be relevant for the modulation of memory formation by novelty.

Dynamic activation of the anterior cingulate cortex during anticipatory anxiety

Based on theoretical models, we investigated the dynamics of brain activation during anticipatory anxiety using functional magnetic resonance imaging and a combined parametric/correlational design. Subjects (16 females) anticipated the application of electrical shocks of varying intensity resulting in four different threat levels. The parametric analysis revealed an inverted U-function of activation in the ventral anterior cingulate cortex (ACC) depending on the level of threat. Furthermore, the correlation analysis showed that the association between anxiety and brain activation in the pregenual ACC was, as a tendency, positive during moderate threat but clearly negative during strong threat. Moreover, during strong threat, a positive correlation between anxiety and activation was observed in the dorsal ACC, somatosensory cortex, motor cortex, and hippocampus. These findings suggest threat dependent dynamics of brain activation in the ACC; with increased attentional avoidance during moderate threat and a switch to hypervigilant action readiness in the most anxious subjects during strong threat.

Modulation of the neural network involved in the processing of anger prosody: the role of task-relevance and social phobia

Individuals with social phobia display neural hyperactivation towards angry facial expressions. However, it is uncertain whether they also show abnormal brain responses when processing angry voices. In an event-related functional magnetic resonance imaging study, we investigated brain responses to neutral and angry voices in 12 healthy control participants and 12 individuals with social phobia when emotional prosody was either task-relevant or task-irrelevant. Regardless of task, both phobic and non-phobic participants recruited a network comprising frontotemporal regions, the amygdala, the insula, and the striatum, when listening to angry compared to neutral prosody. Across participants, increased activation in orbitofrontal cortex during task-relevant as compared to task-irrelevant emotional prosody processing was found. Compared to healthy controls, individuals with social phobia displayed significantly stronger orbitofrontal activation in response to angry versus neutral voices under both task conditions. These results suggest a disorder-associated increased involvement of the orbitofrontal cortex in response to threatening voices in social phobia.