Disrupted effective connectivity between the amygdala and orbitofrontal cortex in social anxiety disorder during emotion discrimination revealed by dynamic causal modeling for FMRI.

Social anxiety disorder (SAD) is characterized by over-reactivity of fear-related circuits in social or performance situations and associated with marked social impairment. We used dynamic causal modeling (DCM), a method to evaluate effective connectivity, to test our hypothesis that SAD patients would exhibit dysfunctions in the amygdala-prefrontal emotion regulation network. Thirteen unmedicated SAD patients and 13 matched healthy controls performed a series of facial emotion and object discrimination tasks while undergoing fMRI. The emotion-processing network was identified by a task-related contrast and motivated the selection of the right amygdala, OFC, and DLPFC for DCM analysis. Bayesian model averaging for DCM revealed abnormal connectivity between the OFC and the amygdala in SAD patients. In healthy controls, this network represents a negative feedback loop. In patients, however, positive connectivity from OFC to amygdala was observed, indicating an excitatory connection. As we did not observe a group difference of the modulatory influence of the FACE condition on the OFC to amygdala connection, we assume a context-independent reduction of prefrontal control over amygdalar activation in SAD patients. Using DCM, it was possible to highlight not only the neuronal dysfunction of isolated brain regions, but also the dysbalance of a distributed functional network.

Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding.

Serotonergic neurotransmission is thought to underlie a dynamic interrelation between different key structures of the serotonin system. The serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft into the neuron, as well as the serotonin-1A (5-HT1A) and -1B (5-HT1B) receptors, inhibitory auto-receptors in the raphe region and projection areas, respectively, are likely to determine serotonin release. Thereby, they are involved in the regulation of extracellular serotonin concentrations and the extent of serotonergic effects in respective projection areas. Complex receptor interactions can be assessed in vivo with positron emission tomography (PET) and single-nucleotide-polymorphisms, which are thought to alter protein expression levels. Due to the complexity of the serotonergic system, gene × gene interactions are likely to regulate transporter and receptor expression and therefore subsequently serotonergic transmission. In this context, we measured 51 healthy subjects (mean age 45.5 ± 12.9, 38 female) with PET using [carbonyl-(11)C]WAY-100635 to determine 5-HT1A receptor binding potential (5-HT1A BPND). Genotyping for rs6296 (HTR1B) and 5-HTTLPR (SERT gene promoter polymorphism) was performed using DNA isolated from whole blood. Voxel-wise whole-brain ANOVA revealed a positive interaction effect of genotype groups (5-HTTLPR: LL, LS+SS and HTR1B: rs6296: CC, GC+GG) on 5-HT1A BPND with peak t-values in the bilateral parahippocampal gyrus. More specifically, highest 5-HT1A BPND was identified for individuals homozygous for both the L-allele of 5-HTTLPR and the C-allele of rs6296. This finding suggests that the interaction between two major serotonergic structures involved in serotonin release, specifically the SERT and 5-HT1B receptor, results in a modification of the inhibitory serotonergic tone mediated via 5-HT1A receptors.

Differential modulation of the default mode network via serotonin-1A receptors.

Reflecting one's mental self is a fundamental process for evaluating the personal relevance of life events and for moral decision making and future envisioning. Although the corresponding network has been receiving growing attention, the driving neurochemical mechanisms of the default mode network (DMN) remain unknown. Here we combined positron emission tomography and functional magnetic resonance imaging to investigate modulations of the DMN via serotonin-1A receptors (5-HT(1A)), separated for 5-HT autoinhibition (dorsal raphe nucleus) and local inhibition (heteroreceptors in projection areas). Using two independent approaches, regional 5-HT(1A) binding consistently predicted DMN activity in the retrosplenial cortex for resting-state functional magnetic resonance imaging and the Tower of London task. On the other hand, both local and autoinhibitory 5-HT(1A) binding inversely modulated the posterior cingulate cortex, the strongest hub in the resting human brain. In the frontal part of the DMN, a negative association was found between the dorsal medial prefrontal cortex and local 5-HT(1A) inhibition. Our results indicate a modulation of key areas involved in self-referential processing by serotonergic neurotransmission, whereas variations in 5-HT(1A) binding explained a considerable amount of the individual variability in the DMN. Moreover, the brain regions associated with distinct introspective functions seem to be specifically regulated by the different 5-HT(1A) binding sites. Together with previously reported modulations of dopamine and GABA, this regional specialization suggests complex interactions of several neurotransmitters driving the default mode network.

Regional differences in SERT occupancy after acute and prolonged SSRI intake investigated by brain PET.

Blocking of the serotonin transporter (SERT) represents the initial mechanism of action of selective serotonin reuptake inhibitors (SSRIs) which can be visualized due to the technical proceedings of SERT occupancy studies. When compared to the striatum, higher SERT occupancy in the midbrain and lower values in the thalamus were reported. This indicates that occupancy might be differently distributed throughout the brain, which is supported by preclinical findings indicating a regionally varying SERT activity and antidepressant drug concentration. The present study therefore aimed to investigate regional SERT occupancies with positron emission tomography and the radioligand [(11)C]DASB in 19 depressed patients after acute and prolonged intake of oral doses of either 10mg/day escitalopram or 20mg/day citalopram. Compared to the mean occupancy across cortical and subcortical regions, we detected increased SERT occupancies in regions commonly associated with antidepressant response, such as the subgenual cingulate, amygdala and raphe nuclei. When acute and prolonged drug intake was compared, SERT occupancies increased in subcortical areas that are known to be rich in SERT. Moreover, SERT occupancy in subcortical brain areas after prolonged intake of antidepressants was predicted by plasma drug levels. Similarly, baseline SERT binding potential seems to impact SERT occupancy, as regions rich in SERT showed greater binding reduction as well as higher residual binding. These findings suggest a region-specific distribution of SERT blockage by SSRIs and relate the postulated link between treatment response and SERT occupancy to certain brain regions such as the subgenual cingulate cortex.

Gray matter and intrinsic network changes in the posterior cingulate cortex after selective serotonin reuptake inhibitor intake.

Preclinical studies have demonstrated that serotonin (5-HT) challenge changes neuronal circuitries and microarchitecture. However, evidence in human subjects is missing. Pharmacologic magnetic resonance imaging (phMRI) applying selective 5-HT reuptake inhibitors (SSRIs) and high-resolution structural and functional brain assessment is able to demonstrate the impact of 5-HT challenge on neuronal network morphology and functional activity. To determine how SSRIs induce changes in gray matter and neuronal activity, we conducted a longitudinal study using citalopram and escitalopram. Seventeen healthy subjects completed a structural and functional phMRI study with randomized, cross-over, placebo-controlled, double-blind design. Significant gray matter increases were observed (among other regions) in the posterior cingulate cortex (PCC) and the ventral precuneus after SSRI intake of 10days, while decreases were observed within the pre- and postcentral gyri (all P<0.05, family-wise error [FWE] corrected). Furthermore, enhanced resting functional connectivity (rFC) within the ventral precuneus and PCC was associated with gray matter increases in the PCC (all FWE Pcorr<0.05). Corroborating these results, whole-brain connectivity density, measuring the brain's functional network hubs, was significantly increased after SSRI-intake in the ventral precuneus and PCC (all FWE Pcorr<0.05). Short-term administration of SSRIs changes gray matter structures, consistent with previous work reporting enhancement of neuroplasticity by serotonergic neurotransmission. Furthermore, increased gray matter in the PCC is associated with increased functional connectivity in one of the brain's metabolically most active regions. Our novel findings provide convergent evidence for dynamic alterations of brain structure and function associated with SSRI pharmacotherapy.

Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression.

Suffering from anhedonia, patients with major depressive disorder (MDD) exhibit alterations in several parts of the serotonergic neurotransmitter system, which are in turn involved in reward processing. However, previous investigations of the serotonin transporter (SERT) focused on regional differences with varying results depending on the clinical syndrome. Here, we aimed to describe the serotonergic system of MDD patients on a network level by evaluating SERT associations across brain regions. Twenty medication free patients with major depression and 20 healthy controls underwent positron emission tomography using the radioligand [(11) C]DASB. SERT binding potentials (BPND ) were quantified voxel-wise with the multilinear reference tissue model 2. In addition, SERT BPND was extracted from the dorsal raphe nucleus (DRN) as an indicator of midbrain serotonergic neurotransmission. Whole-brain linear regression analysis was applied to evaluate the association of DRN SERT bindings to those in projection areas, which was followed by ANCOVA to assess differences in interregional relationships between patients and controls. Although both groups showed widespread positive correlations, group differences were restricted to decreased SERT associations between the DRN and the ventral striatum (right and left respectively: t=5.85, P<0.05 corrected and t=5.07, P<0.1 corrected) when comparing MDD patients (R(2)=0.11 and 0.24) to healthy subjects (R(2)=0.72 and 0.66, P<0.01 and 0.05 corrected). Adjusting for age and sex did not change these findings. This study indicates a disturbed regulation between key regions involved in reward processing via the SERT. Our interregional approach highlights the importance of evaluating pathophysiological alterations on a network level to gain complementary information in addition to regional investigations.

Effects of Silexan on the serotonin-1A receptor and microstructure of the human brain: a randomized, placebo-controlled, double-blind, cross-over study with molecular and structural neuroimaging.

BACKGROUND: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role to the serotonin-1A receptor in the pathogenesis and treatment of anxiety. METHODS: To elucidate the effect of Silexan on serotonin-1A receptor binding, 17 healthy men underwent 2 positron emission tomography measurements using the radioligand [carbonyl-(11)C]WAY-100635 following the daily intake of 160 mg Silexan or placebo for a minimum of 8 weeks (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. RESULTS: Serotonin-1A receptor binding potential was shown to be significantly reduced following the intake of Silexan compared with placebo in 2 large clusters encompassing the temporal gyrus, the fusiform gyrus and the hippocampus on one hand as well as the insula and anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. CONCLUSION: This positron emission tomography study proposes an involvement of the serotonin-1A receptor in the anxiolytic effects of Silexan. The study was registered in the International Standard Randomized Controlled Trial Number Register as ISRCTN30885829 (http://www.controlled-trials.com/isrctn/).

Neurotransmitters and electroconvulsive therapy.

OBJECTIVES: Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatment-refractory depression. However, despite ECT's widespread use, the exact neurobiological mechanisms underlying its efficacy are not fully understood. Over the past 3 decades, extensive work in rodents, primates, and humans has begun to delineate the impact of electroconvulsive seizures (ECS) and ECT on neurotransmission systems commonly implicated in depression. In the current review, we will focus on two major biogenic amine systems, namely serotonin and dopamine. METHODS: The database of PubMed was searched for preclinical studies describing the effects of ECS on the serotonergic and dopaminergic system using behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA and protein expression, electrophysiology, and positron emission tomography. Additionally, human data describing ECT's effects on neurotransmitter turnover, receptor binding, and functional imaging were reviewed together with relevant genetic association studies. RESULTS: Literature research resulted in 40 published original studies related to ECS/ECT and the serotonergic system, whereby only three were studies in humans. Regarding dopamine, 15 preclinical and 12 human studies were found in PubMed database. CONCLUSIONS: Converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier preclinical and clinical findings relating to enhancement of serotonergic neurotransmission and activation of the mesocorticolimbic dopamine system after ECS/ECT. Moreover, it seems that these effects are evident at various levels, including neurotransmitter release, receptor binding, and overall neurotransmission. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT's profound antidepressant effect and would support the development of better pharmacological and somatic treatment approaches for refractory depression.

RESCALE: Voxel-specific task-fMRI scaling using resting state fluctuation amplitude.

The BOLD signal measured in fMRI studies depends not only on neuronal activity, but also on other parameters like tissue vascularization, which may vary between subjects and between brain regions. A correction for variance from vascularization effects can thus lead to improved group statistics by reducing inter-subject variability. The fractional amplitude of low-frequency fluctuations (fALFF) as determined in a resting-state scan has been shown to be dependent on vascularization. Here we present a correction method termed RESCALE (REsting-state based SCALing of parameter Estimates) that uses local information to compute a voxel-wise scaling factor based on the correlation structure of fALFF and task activation parameter estimates from within a cube of 3 × 3 × 3 surrounding that voxel. The scaling method was used on a visuo-motor paradigm and resulted in a consistent increase in t-values in all task-activated cortical regions, with increases in peak t-values of 37.0% in the visual cortex and 12.7% in the left motor cortex. The RESCALE method as proposed herein can be easily applied to all task-based fMRI group studies provided that resting-state data for the same subject group is also acquired.

Serotonin-1A receptor binding is positively associated with gray matter volume -- a multimodal neuroimaging study combining PET and structural MRI.

Animal models revealed that the serotonin-1A (5-HT(1A)) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT(1A) receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT(1A) receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R(2) values ranged from 0.308 to 0.503, p<0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R(2)=0.656, p=0.001). We also observed a broad range between 5-HT(1A) receptor binding and GMV. Given the congruence of altered 5-HT(1A) receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders.