P. Stein

Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder

Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment. Although the amygdala has a central role in perception and processing of threatening cues, little is known about the involved networks and corresponding dysfunctions in social anxiety. Therefore, this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways. Ten patients with anxiety disorders (social and/or panic) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state. Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region. Group comparisons were done by random-effects analysis in SPM. Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus. The strength of this functional connectivity showed a negative association with the severity of state anxiety. In addition, an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group. Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder. Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing.

Area-specific modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI: a randomized cross-over study.

Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the amygdala, medial frontal gyrus, parahippocampal, fusiform and middle temporal gyri. Post-hoc t-tests revealed decreased BOLD-signal in the right amygdala and left parahippocampal gyrus in both pharmacological conditions, compared to placebo. Escitalopram, compared to citalopram, induced a decrease of BOLD-signal in the medial frontal gyrus and an increase in the right fusiform and left parahippocampal gyri. Drug effects were concentrated in brain regions with dense serotonergic projections. Both escitalopram and citalopram attenuated BOLD-signal in the amygdala and parahippocampal cortex to emotionally significant stimuli compared to control stimuli. We believe that reduced reactivity in the medial frontal gyrus found for escitalopram compared to citalopram administration might explain the response differences between study drugs as demonstrated in previous clinical trials.

Influence of escitalopram treatment on 5-HT 1A receptor binding in limbic regions in patients with anxiety disorders.

There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT1A receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT1A receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT1A receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT1A receptor antagonist [carbonyl-11C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2±6.0 mg day−1) for a minimum of 12 weeks. A second PET scan was conducted after 109±27 days. 5-HT1A receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT1A receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT1A binding potential after SSRI treatment.

Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects

Objectives: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5‐HT1A receptor, and sex hormones. Experimental Design: Thirty‐three healthy volunteers (16 women, aged 26.24 ± 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl‐11C]WAY‐100635 to quantify 5‐HT1A binding potentials (BPNDs) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17ß‐estradiol and sex hormone‐binding globulin (SHBG) were measured. Relations between aggression scores, regional 5‐HT1A BPNDs, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. Principal Observations: Statistical analyses revealed higher 5‐HT1A receptor BPNDs in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5‐HT1A BPNDs in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). Conclusions: The present study provides first‐time evidence for a specific interrelation between the 5‐HT1A receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down‐stream control due to higher amounts or activities of frontal 5‐HT1A receptors in more aggressive subjects, which is presumably modulated by sex hormones. Hum Brain Mapp 30:2558–2570, 2009.

Lateralization of the serotonin-1A receptor distribution in language areas revealed by PET

Lateralization is a well described aspect of the human brain. A plethora of morphological, cytological and functional studies describes hemispheric asymmetry in auditory and language areas. However, no study has reported cortical lateralization in the healthy human brain in vivo on the level of neurotransmitter receptors and in relation to functional organization so far. In this study, we assessed the distribution of the main inhibitory serotonergic receptor (the 5-HT1A receptor) and analyzed its regional binding with regard to hemisphere, sex and plasma levels of sex steroid hormones (testosterone, estradiol, progesterone). We quantified the 5-HT1A receptor binding potential by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 and measured hormone levels in thirty-four (16 females, 18 males) healthy right-handed subjects. The obtained data were analyzed in an automated region of interest (ROI) based approach investigating 14 auditory, language and limbic areas. We found significantly higher 5-HT1A receptor binding in the superior and middle frontal gyri of the right hemisphere, the triangular and orbital parts of the inferior frontal gyrus, the supramarginal gyrus, the superior gyrus of the temporal pole and the middle temporal gyrus. Regions of the primary and secondary auditory cortex (Heschls gyrus and superior temporal gyrus) and the Rolandic operculum displayed significantly higher receptor binding in the left hemisphere. 5-HT1A receptor binding was 1.8-2.9% higher in right frontal ROIs and 2-3.6% higher in left primary and secondary auditory regions. There was no hemispheric difference in 5-HT(1A) receptor binding in the hippocampus, amygdala, and insula. Post-hoc testing suggested that lateralization of 5-HT1A receptor binding differed between the sexes in the triangular part of the inferior frontal gyrus. For the first time, this PET study shows lateralization of the main inhibitory receptor of the serotonergic system in functionally asymmetric organized regions of the healthy human brain in vivo.

Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET

Electroconvulsive therapy (ECT) is a potent therapy in severe treatment-refractory depression. Although commonly applied in psychiatric clinical routine since decades, the exact neurobiological mechanism regarding its efficacy remains unclear. Results from preclinical and clinical studies emphasize a crucial involvement of the serotonin-1A receptor (5-HT1A) in the mode of action of antidepressant treatment. This includes associations between treatment response and changes in 5-HT1A function and density by antidepressants. Further, alterations of the 5-HT1A receptor are consistently reported in depression. To elucidate the effect of ECT on 5-HT1A receptor binding, 12 subjects with severe treatment-resistant major depression underwent three positron emission tomography (PET) measurements using the highly selective radioligand [carbonyl-11C]WAY100635, twice before (test–retest variability) and once after 10.08±2.35 ECT sessions. Ten patients (∼83%) were responders to ECT. The voxel-wise comparison of the 5-HT1A receptor binding (BPND) before and after ECT revealed a widespread reduction in cortical and subcortical regions (P<0.05 corrected), except for the occipital cortex and the cerebellum. Strongest reductions were found in regions consistently reported to be altered in major depression and involved in emotion regulation, such as the subgenual part of the anterior cingulate cortex (−27.5%), the orbitofrontal cortex (−30.1%), the amygdala (−31.8%), the hippocampus (−30.6%) and the insula (−28.9%). No significant change was found in the raphe nuclei. There was no significant difference in receptor binding in any region comparing the first two PET scans conducted before ECT. This PET study proposes a global involvement of the postsynaptic 5-HT1A receptor binding in the effect of ECT.

The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635

PurposeThe higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT1A) receptor.MethodsSixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-11C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT1A receptor BPND was quantified using (1) the ‘gold standard’ manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling.ResultsThe 5-HT1A receptor BPND was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BPND values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT1A receptor BPND within both sexes compared to the small mean differences between men and women.ConclusionsTo conclude, when measured in the follicular phase, women do not differ from men in the 5-HT1A receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT1A receptor expression.

Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain

Abstract Objective. Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter. Methods. We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-11C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity). Results. We found a 20–30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days. Conclusions. Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.

Progesterone Level Predicts Serotonin-1A Receptor Binding in the Male Human Brain

Background: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT1A) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT1A receptor binding in healthy male subjects. Methods: Molecular neuroimaging of the 5-HT1A receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. Results: Plasma P levels explained up to 65% of the variability in 5-HT1A receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT1A binding attributed to P. Conclusions: The results of this study provide further support for the effect of P on 5-HT1A receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system.

Effects of hormone replacement therapy on cerebral serotonin-1A receptor binding in postmenopausal women examined with [carbonyl-11C]WAY-100635

Preclinical research points to a strong modulatory influence of gonadal hormones on the serotonin system. However, human data corroborating this association remains scarce. The aim of this study was to examine the effects of hormone replacement therapy on 5-HT₁A receptor binding in postmenopausal women using positron emission tomography (PET) and the radioligand [carbonyl-(11)C]WAY-100635. In this randomized, double-blind, longitudinal study, 30 postmenopausal women underwent treatment with either a combination of oral 17β-estradiol valerate and micronized progesterone (group 1, n=10), oral 17β-estradiol valerate (group 2, n=10), or placebo (group 3, n=10). Two PET measurements were performed, one the day before treatment start and the second after at least eight weeks of treatment. Plasma levels of estradiol (E₂), progesterone (P₄), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were collected prior to PET measurements. As expected, hormone replacement therapy led to a significant increase in E₂ and P4 plasma levels in group 1 and to a significant increase in E₂ levels in group 2. The 5-HT₁A receptor binding did not change significantly after estrogen, combined estrogen/progesterone treatment or placebo in any of the investigated brain regions. There were no significant correlations between changes in E₂ or P4 values and changes in 5-HT₁A receptor binding. Although we were not able to confirm effects of gonadal hormone treatment on 5-HT₁A receptor binding, our data do not preclude associations between sex steroid levels and serotonin, the neurotransmitter implicated most strongly in the pathogenesis of affective and anxiety disorders. ClinicalTrials.gov Identifier: NCT00755963.