Fredrik Åhs

Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo.

BACKGROUND Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia. METHODS Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale. RESULTS Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction. CONCLUSIONS Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.

A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

High-frequency heart rate variability and cortico-striatal activity in men and women with social phobia.

Identifying brain systems that regulate or modulate autonomic nervous system functions may identify pathways through which psychosocial factors can influence health and disease. Reduced high-frequency heart rate variability (HF-HRV) characterizes anxiety disordered patients and is predictive of adverse myocardial events. Sex differences in the prevalence of anxiety disorders and cardiac diseases implicate the possibility of sex specific neural regulation of HF-HRV. We investigated the correlation between HF-HRV and regional cerebral blood flow (rCBF) in 28 subjects (15 women) with social phobia undergoing a stressful public speaking task. Regional CBF was measured with [(15)O] water positron emission tomography. Stress induced rCBF correlated positively with HF-HRV in the right supra genual anterior cingulate cortex Brodmanns area (BA) 32, the right head of the caudate nucleus and bilaterally in the medial prefrontal cortex (BA10), extending into the dorsolateral prefrontal cortex (BA46) in the left hemisphere. Men showed larger positive co-variation in the caudate than women. These findings underscore the importance of the emotional division of the anterior cingulate cortex, the prefrontal cortex and the striatum in cardiovagal activity. The study replicates and extends results from published functional neuroimaging studies on cardioregulatory or modulatory areas in healthy subjects to men and women with social phobia. Moreover, caudate functions, possibly related to dopaminergic neurotransmission, have sexually dimorphic effects on vagal modulation of the heart.

Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake phobia.

The objective was to study effects of fear on brain activity, functional connectivity and brain-behavior relationships during symptom provocation in subjects with specific phobia. Positron emission tomography (PET) and (15)O water was used to measure regional cerebral blood flow (rCBF) in 16 women phobic of either snakes or spiders but not both. Subjects watched pictures of snakes and spiders serving either as phobic or fear-relevant, but non-phobic, control stimuli depending on phobia type. Presentation of phobic as compared with non-phobic cues was associated with increased activation of the right amygdala and cerebellum as well as the left visual cortex and circumscribed frontal areas. Activity decreased in the prefrontal, orbitofrontal and ventromedial cortices as well as in the primary somatosensory cortex and auditory cortices. Furthermore, amygdala activation correlated positively with the subjective experience of distress. Connectivity analyses of activity in the phobic state revealed increased functional couplings between voxels in the right amygdala and the periamygdaloid area, fusiform gyrus and motor cortex. During non-phobic stimulation, prefrontal activity correlated negatively with amygdala rCBF, suggesting a phobia-related functional decoupling. These results suggest that visually elicited phobic reactions activate object recognition areas and deactivate prefrontal areas involved in cognitive control over emotion-triggering areas like the amygdala, resulting in motor readiness to support fight or flight.

Hypothalamic blood flow correlates positively with stress-induced cortisol levels in subjects with social anxiety disorder.

Objective: The adrenal excretion of cortisol in animals is dependent on the production of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus. The a priori hypothesis of this study was that hypothalamic regional cerebral blood flow (rCBF) would correlate positively with salivary cortisol levels in patients with social anxiety disorder (SAD) during anxiety provocation. Another objective was to evaluate whether salivary cortisol levels correlated with rCBF in other brain areas. Method: Regional CBF was measured with oxygen-15-labeled water and positron emission tomography during a public speaking task before and after placebo treatment in 12 subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined SAD. Cortisol concentrations in saliva were measured 15 minutes after the task. The a priori hypothesis of a salivary cortisol-dependent activation of the hypothalamus was studied with region-of-interest analysis. In addition, the covariation between rCBF and salivary cortisol was studied in the whole brain using the general linear model. Results: The region-of-interest analysis revealed a positive correlation between salivary cortisol and hypothalamic rCBF. In the whole brain analysis, a positive covariation between rCBF and salivary cortisol levels was found in a midbrain cluster encompassing the hypothalamus with its statistical maximum in the mamillary bodies. Negative covariations were observed in the medial prefrontal cortex as well as in the motor and premotor cortices. Conclusion: Like in animals, stress-induced cortisol excretion in humans may be inhibited by activity in the medial prefrontal cortex and enhanced by activity in the hypothalamus. ACC = anterior cingulate cortex; ACTH = adrenocorticotropic hormone; BA = Brodmann area; CRF = corticotropin-releasing factor; fMRI = functional magnetic resonance imaging; MNI = Montreal Neurological Institute; MTL = medial temporal lobe; PET = positron emission tomography; PTSD = posttraumatic stress disorder; PVN = paraventricular nucleus of the hypothalamus; rCBF = regional cerebral blood flow; ROI = region of interest; SAD = social anxiety disorder.

Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6–8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.

Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.

IMPORTANCE Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively. OBJECTIVE To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB. DESIGN, SETTING, AND PARTICIPANTS We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014. MAIN OUTCOMES AND MEASURES The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms. RESULTS The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected). CONCLUSIONS AND RELEVANCE Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

Aversive learning increases sensory detection sensitivity.

Increased sensitivity to specific cues in the environment is common in anxiety disorders. This increase in sensory processing can emerge through attention processes that enhance discrimination of a cue from other cues as well as through augmented senses that reduce the absolute intensity of sensory stimulation needed for detection. Whereas it has been established that aversive conditioning can enhance odor quality discrimination, it is not known whether it also changes the absolute threshold at which an odor can be detected. In two separate experiments, we paired one odor of an indistinguishable odor pair with an aversive outcome using a classical conditioning paradigm. Ability to discriminate and to detect the paired odor was assessed before and after conditioning. The results demonstrate that aversive conditioning increases absolute sensory sensitivity to a predictive odor cue in an odor-specific manner, rendering the conditioned odor detectable at a significantly lower (20%) absolute concentration. As animal research has found long-lasting change in behavior and neural signaling resulting from conditioning, absolute threshold was also tested eight weeks later. Detection threshold had returned to baseline level at the eight week follow-up session suggesting that the change in detection threshold was mediated by a transient reorganization. Taken together, we can for the first time demonstrate that increasing the biological salience of a stimulus augments the individuals absolute sensitivity in a stimulus-specific manner outside conscious awareness. These findings provide a unique framework for understanding sensory mechanisms in anxiety disorders as well as further our understanding of mechanisms underlying classical conditioning.

Extinction in multiple virtual reality contexts diminishes fear reinstatement in humans

Although conditioned fear can be effectively extinguished by unreinforced exposure to a threat cue, fear responses tend to return when the cue is encountered some time after extinction (spontaneous recovery), in a novel environment (renewal), or following presentation of an aversive stimulus (reinstatement). As extinction represents a context-dependent form of new learning, one possible strategy to circumvent the return of fear is to conduct extinction across several environments. Here, we tested the effectiveness of multiple context extinction in a two-day fear conditioning experiment using 3-D virtual reality technology to create immersive, ecologically-valid context changes. Fear-potentiated startle served as the dependent measure. All three experimental groups initially acquired fear in a single context. A multiple extinction group then underwent extinction in three contexts, while a second group underwent extinction in the acquisition context and a third group underwent extinction in a single different context. All groups returned 24h later to test for return of fear in the extinction context (spontaneous recovery) and a novel context (renewal and reinstatement/test). Extinction in multiple contexts attenuated reinstatement of fear but did not reduce spontaneous recovery. Results from fear renewal were tendential. Our findings suggest that multi-context extinction can reduce fear relapse following an aversive event--an event that often induces return of fear in real-world settings--and provides empirical support for conducting exposure-based clinical treatments across a variety of environments.

Medial prefrontal pathways for the contextual regulation of extinguished fear in humans

The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.