Anna Höflich

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

Reflecting ones 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-HT1A), separated for 5-HT autoinhibition (dorsal raphe nucleus) and local inhibition (heteroreceptors in projection areas). Using two independent approaches, regional 5-HT1A 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-HT1A 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-HT1A inhibition. Our results indicate a modulation of key areas involved in self-referential processing by serotonergic neurotransmission, whereas variations in 5-HT1A 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-HT1A 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.

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.

Increased Neural Habituation in the Amygdala and Orbitofrontal Cortex in Social Anxiety Disorder Revealed by fMRI

A characterizing symptom of social anxiety disorder (SAD) is increased emotional reactivity towards potential social threat in combination with impaired emotion and stress regulation. While several neuroimaging studies have linked SAD with hyperreactivity in limbic brain regions when exposed to emotional faces, little is known about habituation in both the amygdala and neocortical regulation areas. 15 untreated SAD patients and 15 age- and gender-matched healthy controls underwent functional magnetic resonance imaging during repeated blocks of facial emotion () and object discrimination tasks (). Emotion processing networks were defined by a task-related contrast (). Linear regression was employed for assessing habituation effects in these regions. In both groups, the employed paradigm robustly activated the emotion processing and regulation network, including the amygdalae and orbitofrontal cortex (OFC). Statistically significant habituation effects were found in the amygdalae, OFC, and pulvinar thalamus of SAD patients. No such habituation was found in healthy controls. Concurrent habituation in the medial OFC and the amygdalae of SAD patients as shown in this study suggests intact functional integrity and successful short-term down-regulation of neural activation in brain areas responsible for emotion processing. Initial hyperactivation may be explained by an insufficient habituation to new stimuli during the first seconds of exposure. In addition, our results highlight the relevance of the orbitofrontal cortex in social anxiety disorders.

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.

Imaging treatment effects in depression

Abstract In the past years a multitude of studies has revealed alterations on a neuromolecular, structural and network level in patients with major depressive disorder within key regions of emotion and cognition processing as well as implicated neurotransmitter systems. The present review is thought to give an overview over recent developments with regard to treatment-induced changes in structural, functional and molecular neuroimaging. A number of studies could show that antidepressant treatment may lead to a partial restorage of primarily altered processes. This becomes evident in structural magnetic resonance imaging studies which point towards the reduction of volumetric differences between depressed patients and healthy controls during treatment, along with a normalization of neuronal functioning as assessed with functional magnetic resonance imaging. On a molecular level positron emission tomography studies investigating targets which are fundamentally implicated in antidepressant action such as serotonergic and dopaminergic transporters and receptors have shown to be sustainably influenced by antidepressant treatment. However, it seems that not all dysfunctional processes can be reversed by antidepressant treatment and that state and trait factors are evident not only on a behavioral but also on a neurobiological level.

High-resolution functional MRI of the human amygdala at 7 T

Functional magnetic resonance imaging (fMRI) has become the primary non-invasive method for investigating the human brain function. With an increasing number of ultra-high field MR systems worldwide possibilities of higher spatial and temporal resolution in combination with increased sensitivity and specificity are expected to advance detailed imaging of distinct cortical brain areas and subcortical structures. One target region of particular importance to applications in psychiatry and psychology is the amygdala. However, ultra-high field magnetic resonance imaging of these ventral brain regions is a challenging endeavor that requires particular methodological considerations. Ventral brain areas are particularly prone to signal losses arising from strong magnetic field inhomogeneities along susceptibility borders. In addition, physiological artifacts from respiration and cardiac action cause considerable fluctuations in the MR signal. Here we show that, despite these challenges, fMRI data from the amygdala may be obtained with high temporal and spatial resolution combined with increased signal-to-noise ratio. Maps of neural activation during a facial emotion discrimination paradigm at 7 T are presented and clearly show the gain in percental signal change compared to 3 T results, demonstrating the potential benefits of ultra-high field functional MR imaging also in ventral brain areas.

Ketamine-Induced Modulation of the Thalamo- Cortical Network in Healthy Volunteers As a Model for Schizophrenia

Background: Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-d-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity. Methods: Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design. Results: Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. Conclusions: Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.

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 [11C]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 (R2 = 0.11 and 0.24) to healthy subjects (R2 = 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. Hum Brain Mapp 35:3857–3866, 2014.

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-11C]WAY-100635 following the daily intake of 160mg 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/).

Stability of low-frequency fluctuation amplitudes in prolonged resting-state fMRI

The (fractional) amplitudes of low-frequency fluctuations (f)ALFF are popular measures for the magnitude of low-frequency oscillations in resting-state fMRI (R-fMRI) data. Both measures can be directly derived from the spectral power of R-fMRI time courses. Numerous studies suggest that ALFF and fALFF might be used as biomarkers for a variety of diseases including schizophrenia, major depressive disorder, and obsessive-compulsive disorder. However, the temporal stability of (f)ALFF values, which is of great importance for the application of (f)ALFF both as a biomarker and scaling parameter, has not been studied in detail yet. Here, we quantify the temporal stability, robustness and reproducibility of both ALFF and fALFF maps obtained from R-fMRI data by performing statistical analyses over 55 minute resting-state scans which included a period of NaCl infusion. We also examine the differences of using either raw or standardised (f)ALFF maps. Our analyses show that no significant changes of (f)ALFF values over the 55minute period occur for both raw and standardised (f)ALFF maps. In addition, we demonstrate that raw (f)ALFF maps across subjects are correlated with head motion as quantified via frame-wise displacement, whereas no such correlation is present in standardised (f)ALFF maps. In conclusion, the results of our study show that both ALFF and fALFF qualify as potential biomarkers due to their high temporal stability.