- Email: [email protected]
P.1.e.027 Serotonin -1A receptor binding in the dorsal raphe nucleus is associated with hippocampal grey matter volume
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P.1.e. Basic and clinical neuroscience − Brain imaging
a quantitative analysis in Neuroguide Deluxe v. 2.6 software was performed to evaluate the effect on power spectra, EEG coherence and phase locking in delta (1−4 Hz), theta (4−8 Hz), alpha (8−12 Hz), beta (12−25 Hz), high beta (25−30 Hz) and gamma (30−40 Hz) bands. Power spectral analysis of passive parts of the EEG signal showed that ketamine increased EEG power in high beta and gamma bands, on the contrary psilocin decreased the power throughout the spectral range. The coherence analysis showed an overall decrease in coherence and phase locking in both models. Subsequently, we have compared the signal of active versus passive behavior from baseline recordings of all groups. This analysis revealed that active behavior was associated with an increase of the power in theta and alpha bands and a decrease in the delta band. The same trend in changes was observed in EEG coherence, which increased during active behavior and partly also in the phase locking. Finally, comparisons of active versus passive behavior after the administration of ketamine as well as psilocin revealed a comparable pattern of change. During the active behavior the EEG power increased in all spectral bands and a similar (increased) pattern of changes was observed for coherence and phase locking. During passive behavior, which mimics the resting conditions in humans, both drugs induced increases or decreases in EEG power and decreases in coherence and phase locking. Further analyses revealed that the behavioral activity of rats may confound the final results. It showed that activity is associated with an increase in the power, coherence and phase locking independently of the treatment used. Our results are crucial for further animal studies on EEG and may contribute to the creation of animal guidelines for EEG recording and analysis with a translational impact. Disclosure statement: This work is supported by projects IGA MHCR NR-8792−3, NR-8785−3, CNS MSMT1M0517, MZ 0PCP2005 and GACR 309/09/H072.
P.1.e.026 Influence of catecholamine depletion on the striatal activation associated with appetitive conditioning C. Martin Soelch1 ° , J. Szczepanik2 , S. Fromm2 , W.C. Drevets3 . 1 University Hospital, Department of Psychiatry and Psychotherapy, Zurich, Switzerland; 3 Oklahoma University College of Medicine Laureate Institute for Brain Research, Department of Psychiatry, Tulsa, USA Background and Aims: Appetitive conditioning is the process by which associations between sensory stimuli and positive reinforcement are initially learned. Previous neuroimaging studies in human showed that appetitive conditioning tasks elicit increased hemodynamic activity in regions receiving extensive innervation from the mesolimbic dopamine system, including the ventral striatum, amygdala, anterior cingulate and orbitofrontal cortex [1]. While studies in experimental animals showed that dopamine is involved in this process [2], the influence of DA function on the neural activity underlying appetitive conditioning has not been studied in humans yet. We used here dietary depletion of the catecholamine precursors tyrosine and phenylalanine − a validated method for non-invasively manipulating central dopamine concentrations − to induce a transient reduction in cerebral dopamine concentrations [3]. We hypothesized that tyrosine/phenylalanine depletion would reduce hemodynamic responses to appetitive conditioning in the dopamine-related brain regions that are activated by appetitive conditioning tasks.
Methods: Ten healthy subjects (4 women; mean age 30±4 years) were tested using a double-blind, placebo-controlled, crossover design. On two occasions subjects received, in randomized order, an amino acid drink balanced with tyrosine/ phenylalanine, or an amino acid drink deficient in tyrosine and phenylalanine. Subjects fasted from midnight before the scanning day. Venous blood was sampled at baseline and before and after scanning, and assayed for amino acid concentrations. We assessed emotion and alertness with visual analogue scales and depressive symptoms using clinical scales at times corresponding to the blood sampling. Five hours after administration of the amino acid drink, fMRI scans were acquired using a 3T MRI scanner (EPI sequence, TE: 23ms, TR: 3s, slice thickness: 3.5 mm), while subjects performed an event-related, conditioning task. During the task, pictures of specific fruits, the conditioned stimuli (CS), were associated with monetary gain or loss (US) or with no monetary consequence (neutral condition). We used a 50% partial reinforcement strategy to assess hemodynamic responses to the CS in the absence of the US. Changes in the BOLD signal were compared in two contrasts: appetitive CSunpaired vs CSneutral for appetitive learning and aversive CSunpaired versus CSneutral for aversive learning. Results: The depletion induced significant mood changes, as subjects showed less contentedness and more depressive symptoms and tyrosine, and phenylalanine plasma concentrations were significantly lower in the depletion condition relative to the placebo condition. In contrast, depletion did not significantly alter appetitive learning at a behavioral level. Nevertheless, the BOLD response to appetitive conditioning was significantly reduced in the depleted versus the placebo conditions in ventral and dorsal striatum, anterior cingulate, superior frontal gyrus, inferior parietal lobule, postcentral gyrus and fusiform gyrus. Only the cerebellum evidenced significant greater activation in the depleted versus placebo conditions. Conclusion: Our results showed that tyrosine/phenylalanine depletion diminished hemodynamic activation in regions associated with the mesolimbic dopaminergic system, such as the striatum and anterior cingulate, indicating for the first time in humans the influence of mesolimbic dopamine function on the neural activity underlying appetitive conditioning. References [1] Martin-Soelch, C., Linthicum J., Ernst M., 2007 Appetitive conditioning: neural bases and implications for psychopathology. Neurosci Biobehav Rev 31(3), 426−40. [2] Parkinson, J.A., Cardinal, R.N., Everitt, B.J., 2000 Limbic corticalventral striatal systems underlying appetitive conditioning. Progress in Brain Research 126, 263−85. [3] Harmer, C.J., et al., 2001 Tyrosine depletion attenuate dopamine dunction in healthy volunteers. Psychopharmacology 154, 105−11.
P.1.e.027 Serotonin-1A receptor binding in the dorsal raphe nucleus is associated with hippocampal grey matter volume C. Kraus1 ° , A. Hahn1 , M. Savli1 , A. H¨oflich1 , P. Baldinger1 , G.S. Kranz1 , M. Mitterhauser2 , W. Wadsak2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Biological Psychiatry, Vienna, Austria; 2 Medical University of Vienna, Nuclear Medicine, Vienna, Austria Introduction: Alterations of the main inhibitory serotonergic (5-HT1A ) receptor have been frequently reported in major depressive disorder (MDD) and anxiety disorders [1]. 5-HT1A receptors show highest densities in the dorsal raphe nucleus (DRN), where
P.1.e. Basic and clinical neuroscience − Brain imaging their activation as autoreceptors suppresses the neuronal firing and decreases the synthesis and release of serotonin. Projecting serotonergic neurons from the raphe nuclei mediate an inhibitory serotonergic influence by postsynaptic 5-HT1A heteroreceptors expressed mostly on glutamatergic and GABAergic neurons, especially in the hippocampus, frontal, entorhinal and cingulate cortices. Further evidence demonstrates the role of serotonin in neuroplasticity [2]. Therefore, the aim of this study was to investigate the influence of 5-HT1A receptor binding in the dorsal raphe nucleus on the local grey matter volume (GMV) of regional brain areas. Methods: PET with the highly selective and specific radioligand [carbonyl-11 C]WAY-100635 was used to quantify the 5-HT1A receptor binding (BPND ) in 35 healthy subjects (mean age 27.1±6.7 years; 17 women). The DRN was delineated by a region of interest atlas. Voxel-based morphometry (VBM) analysis of structural MRI data was performed with DARTEL-segmented GMV images as implemented in SPM8 (www.fil.ion.ucl.ac.uk/spm/). Regression analysis was calculated in SPM8 (p < 0.001, uncorrected) using the 5-HT1A BPND of the DRN as independent variable and GMV as dependant variable, with total GMV, sex, age and total injected radiotracer dose as covariates. Results: We found a significant positive correlation between the 5-HT1A BPND in the DRN and the regional GMV in both hippocampal heads (right: peak T = 4.31, MNI x/y/z = 35/−9/−17 mm; cluster volume 488 cm2 ; left: peak T = 3.95, MNI x/y/z = ‐27/−11/−17 mm; cluster volume 304 cm2 ). Further positive correlations were in the left medial temporal lobe (peak T = 3.98, MNI x/y/z = −51/−48/−8 mm; cluster volume 720 cm2 ). Significant negative correlations were found bilaterally in the inferior orbitofrontal cortex (peak right: T = 3.77, MNI x/y/z = 30/30/−17 mm; cluster volume 296 cm2 ; left: peak T = 3.6, MNI x/y/z = −42/32/−15 mm; cluster volume 128 cm2 ) and in the right medial orbitofrontal cortex (peak T = 3.58, MNI x/y/z = 9/66/−15 mm; cluster volume 144 cm2 ). Conclusions: Our findings demonstrate significant relationships with an emphasis on positive correlations between the DRN 5-HT1A receptor binding and grey matter volume in regions receiving major serotonergic innervation from the raphe nuclei, namely the hippocampal heads and the left temporal lobe. Recent data demonstrated 5-HT1A receptor dependant intracellular signaling pathways such as MAPK and Akt that mediate neuronal development and cell survival. This highlights the role of the serotonergic system in neuroplastic processes known to be altered in MDD and anxiety disorders [3]. Concordant to our results, VBM-studies found a reduction of hippocampal GMV in MDD and a reduction of medial temporal lobe GMV in anxiety disorders. To conclude, our results confirm the role of serotonergic neuronal transmission in cytoarchitectonic processes within regions involved in the modulation of mood and provide an explanatory approach for structural and functional alterations found in MDD and anxiety disorders. References [1] Akimova, E., Lanzenberger, R., Kasper, S., 2009 The serotonin-1A receptor in anxiety disorders. Biological Psychiatry 66, 627−35. [2] Vetencourt, M., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., O’Leary, O.F., Castren E., Mattei, L., 2008 The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385−8. [3] van Tol, M.J., van der Wee, N.J.A., van den Heuvel, O.A., Nielen, M.M.A, Demenescu, L.R., Aleman, A., Renken, R., van Buchem, M.A., Zitman, F.G., Veltman, D.J., 2010 Regional brain volume in depression and anxiety disorders. Archives of General Psychiatry 67, 1002−11.
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P.1.e.028 Resting-state functional connectivity of the raphe nuclei A. Hoeflich1 ° , A. Hahn1 , C. Kraus1 , P. Baldinger1 , G.S. Kranz1 , J. Losak1 , C. Windischberger2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, MR Center of Excellence-Center for Medical Physics and Biomedical Engineering, Vienna, Austria Aim of the study: It is well established that the serotonergic system originating in the raphe nuclei plays a decisive role both in psychiatric disorders such as depression and anxiety disorders and in the therapeutic efficacy of SSRIs. Several fMRI studies have focused on the detection of resting-state networks and lately seven bilateral networks covering 80% of the gray matter volume have been identified and linked to a set of major cortical and subcortical hubs [1]. Since cortical structure and function is influenced by modulatory neurotransmitters such as serotonin the aim of the present study was to investigate resting-state functional connectivity of the dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN) as the main serotonergic nuclei projecting to cortical and subcortical areas. Methods: 29 healthy volunteers (12 men, 17 women, 27.5±7 years) underwent a resting-state functional MR scan at 3 Tesla (Medspec S300 MR 163 Scanner; Bruker Biospin, Germany) lasting for 6 minutes. Analysis of functional connectivity data was performed as previously described [2]. Briefly, preprocessing included motion correction, normalization to MNI space and correction for ventricular, white matter and global signal. DRN and MRN were selected as seed regions based on anatomical studies, computing voxel-wise cross-correlation between seed regions and the entire brain. One sample t-tests were carried out in SPM8 for each seed region separately. To investigate differences between DRN and MRN connectivity a repeated measures ANOVA controlling for sex was performed. All statistical tests were carried out two-tailed with a significance level of p < 0.05, FDR-corrected. Results: Functional connectivity analysis of the DRN revealed a significant association with the anterior cingulate cortex (ACC) (t = 5.52, 4/44/4 mm MNI space) and the thalamus bilaterally (left: t = 5.55, −14/8/2 mm; right: t = 7.24, 14/−4/0 mm) extending into the globus pallidus. Comparably, the MRN showed a significant association to the ACC (t = 3.86, 4/40/−4 mm). Direct comparison between the two seed regions showed significantly higher functional connectivity of the DRN with the precuneus (t = 5.05, 2/−70/48 mm) and the thalamus bilaterally (left: t = 3.82, −16/−18/8 mm, right: t = 4.49, 14/−20/6 mm). No significant differences were attained in the ACC. All reported t-values survived FDR correction. Conclusion: In concordance with preclinical data, the results of this investigation indicate that the raphe nuclei may have a differential modulatory influence on cortical and subcortical areas. Hence, this modulation seems to be area-specific with the DRN being significantly stronger connected to the thalamus and the precuneus, a region which has been lately identified as major cortical hub in the default-mode network [1]. The retrieved results fit well in the context of previous studies emphasizing a reciprocal regulative relationship between frontal brain areas and the raphe nuclei [3] and point toward a modulatory function of the serotonergic system on brain areas implicated in the processing of emotion and cognition such as the ACC and the thalamus. This modulatory influence of DRN and MRN may be altered in affective disorders.
P.1.e. Basic and clinical neuroscience − Brain imaging
a quantitative analysis in Neuroguide Deluxe v. 2.6 software was performed to evaluate the effect on power spectra, EEG coherence and phase locking in delta (1−4 Hz), theta (4−8 Hz), alpha (8−12 Hz), beta (12−25 Hz), high beta (25−30 Hz) and gamma (30−40 Hz) bands. Power spectral analysis of passive parts of the EEG signal showed that ketamine increased EEG power in high beta and gamma bands, on the contrary psilocin decreased the power throughout the spectral range. The coherence analysis showed an overall decrease in coherence and phase locking in both models. Subsequently, we have compared the signal of active versus passive behavior from baseline recordings of all groups. This analysis revealed that active behavior was associated with an increase of the power in theta and alpha bands and a decrease in the delta band. The same trend in changes was observed in EEG coherence, which increased during active behavior and partly also in the phase locking. Finally, comparisons of active versus passive behavior after the administration of ketamine as well as psilocin revealed a comparable pattern of change. During the active behavior the EEG power increased in all spectral bands and a similar (increased) pattern of changes was observed for coherence and phase locking. During passive behavior, which mimics the resting conditions in humans, both drugs induced increases or decreases in EEG power and decreases in coherence and phase locking. Further analyses revealed that the behavioral activity of rats may confound the final results. It showed that activity is associated with an increase in the power, coherence and phase locking independently of the treatment used. Our results are crucial for further animal studies on EEG and may contribute to the creation of animal guidelines for EEG recording and analysis with a translational impact. Disclosure statement: This work is supported by projects IGA MHCR NR-8792−3, NR-8785−3, CNS MSMT1M0517, MZ 0PCP2005 and GACR 309/09/H072.
P.1.e.026 Influence of catecholamine depletion on the striatal activation associated with appetitive conditioning C. Martin Soelch1 ° , J. Szczepanik2 , S. Fromm2 , W.C. Drevets3 . 1 University Hospital, Department of Psychiatry and Psychotherapy, Zurich, Switzerland; 3 Oklahoma University College of Medicine Laureate Institute for Brain Research, Department of Psychiatry, Tulsa, USA Background and Aims: Appetitive conditioning is the process by which associations between sensory stimuli and positive reinforcement are initially learned. Previous neuroimaging studies in human showed that appetitive conditioning tasks elicit increased hemodynamic activity in regions receiving extensive innervation from the mesolimbic dopamine system, including the ventral striatum, amygdala, anterior cingulate and orbitofrontal cortex [1]. While studies in experimental animals showed that dopamine is involved in this process [2], the influence of DA function on the neural activity underlying appetitive conditioning has not been studied in humans yet. We used here dietary depletion of the catecholamine precursors tyrosine and phenylalanine − a validated method for non-invasively manipulating central dopamine concentrations − to induce a transient reduction in cerebral dopamine concentrations [3]. We hypothesized that tyrosine/phenylalanine depletion would reduce hemodynamic responses to appetitive conditioning in the dopamine-related brain regions that are activated by appetitive conditioning tasks.
Methods: Ten healthy subjects (4 women; mean age 30±4 years) were tested using a double-blind, placebo-controlled, crossover design. On two occasions subjects received, in randomized order, an amino acid drink balanced with tyrosine/ phenylalanine, or an amino acid drink deficient in tyrosine and phenylalanine. Subjects fasted from midnight before the scanning day. Venous blood was sampled at baseline and before and after scanning, and assayed for amino acid concentrations. We assessed emotion and alertness with visual analogue scales and depressive symptoms using clinical scales at times corresponding to the blood sampling. Five hours after administration of the amino acid drink, fMRI scans were acquired using a 3T MRI scanner (EPI sequence, TE: 23ms, TR: 3s, slice thickness: 3.5 mm), while subjects performed an event-related, conditioning task. During the task, pictures of specific fruits, the conditioned stimuli (CS), were associated with monetary gain or loss (US) or with no monetary consequence (neutral condition). We used a 50% partial reinforcement strategy to assess hemodynamic responses to the CS in the absence of the US. Changes in the BOLD signal were compared in two contrasts: appetitive CSunpaired vs CSneutral for appetitive learning and aversive CSunpaired versus CSneutral for aversive learning. Results: The depletion induced significant mood changes, as subjects showed less contentedness and more depressive symptoms and tyrosine, and phenylalanine plasma concentrations were significantly lower in the depletion condition relative to the placebo condition. In contrast, depletion did not significantly alter appetitive learning at a behavioral level. Nevertheless, the BOLD response to appetitive conditioning was significantly reduced in the depleted versus the placebo conditions in ventral and dorsal striatum, anterior cingulate, superior frontal gyrus, inferior parietal lobule, postcentral gyrus and fusiform gyrus. Only the cerebellum evidenced significant greater activation in the depleted versus placebo conditions. Conclusion: Our results showed that tyrosine/phenylalanine depletion diminished hemodynamic activation in regions associated with the mesolimbic dopaminergic system, such as the striatum and anterior cingulate, indicating for the first time in humans the influence of mesolimbic dopamine function on the neural activity underlying appetitive conditioning. References [1] Martin-Soelch, C., Linthicum J., Ernst M., 2007 Appetitive conditioning: neural bases and implications for psychopathology. Neurosci Biobehav Rev 31(3), 426−40. [2] Parkinson, J.A., Cardinal, R.N., Everitt, B.J., 2000 Limbic corticalventral striatal systems underlying appetitive conditioning. Progress in Brain Research 126, 263−85. [3] Harmer, C.J., et al., 2001 Tyrosine depletion attenuate dopamine dunction in healthy volunteers. Psychopharmacology 154, 105−11.
P.1.e.027 Serotonin-1A receptor binding in the dorsal raphe nucleus is associated with hippocampal grey matter volume C. Kraus1 ° , A. Hahn1 , M. Savli1 , A. H¨oflich1 , P. Baldinger1 , G.S. Kranz1 , M. Mitterhauser2 , W. Wadsak2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Biological Psychiatry, Vienna, Austria; 2 Medical University of Vienna, Nuclear Medicine, Vienna, Austria Introduction: Alterations of the main inhibitory serotonergic (5-HT1A ) receptor have been frequently reported in major depressive disorder (MDD) and anxiety disorders [1]. 5-HT1A receptors show highest densities in the dorsal raphe nucleus (DRN), where
P.1.e. Basic and clinical neuroscience − Brain imaging their activation as autoreceptors suppresses the neuronal firing and decreases the synthesis and release of serotonin. Projecting serotonergic neurons from the raphe nuclei mediate an inhibitory serotonergic influence by postsynaptic 5-HT1A heteroreceptors expressed mostly on glutamatergic and GABAergic neurons, especially in the hippocampus, frontal, entorhinal and cingulate cortices. Further evidence demonstrates the role of serotonin in neuroplasticity [2]. Therefore, the aim of this study was to investigate the influence of 5-HT1A receptor binding in the dorsal raphe nucleus on the local grey matter volume (GMV) of regional brain areas. Methods: PET with the highly selective and specific radioligand [carbonyl-11 C]WAY-100635 was used to quantify the 5-HT1A receptor binding (BPND ) in 35 healthy subjects (mean age 27.1±6.7 years; 17 women). The DRN was delineated by a region of interest atlas. Voxel-based morphometry (VBM) analysis of structural MRI data was performed with DARTEL-segmented GMV images as implemented in SPM8 (www.fil.ion.ucl.ac.uk/spm/). Regression analysis was calculated in SPM8 (p < 0.001, uncorrected) using the 5-HT1A BPND of the DRN as independent variable and GMV as dependant variable, with total GMV, sex, age and total injected radiotracer dose as covariates. Results: We found a significant positive correlation between the 5-HT1A BPND in the DRN and the regional GMV in both hippocampal heads (right: peak T = 4.31, MNI x/y/z = 35/−9/−17 mm; cluster volume 488 cm2 ; left: peak T = 3.95, MNI x/y/z = ‐27/−11/−17 mm; cluster volume 304 cm2 ). Further positive correlations were in the left medial temporal lobe (peak T = 3.98, MNI x/y/z = −51/−48/−8 mm; cluster volume 720 cm2 ). Significant negative correlations were found bilaterally in the inferior orbitofrontal cortex (peak right: T = 3.77, MNI x/y/z = 30/30/−17 mm; cluster volume 296 cm2 ; left: peak T = 3.6, MNI x/y/z = −42/32/−15 mm; cluster volume 128 cm2 ) and in the right medial orbitofrontal cortex (peak T = 3.58, MNI x/y/z = 9/66/−15 mm; cluster volume 144 cm2 ). Conclusions: Our findings demonstrate significant relationships with an emphasis on positive correlations between the DRN 5-HT1A receptor binding and grey matter volume in regions receiving major serotonergic innervation from the raphe nuclei, namely the hippocampal heads and the left temporal lobe. Recent data demonstrated 5-HT1A receptor dependant intracellular signaling pathways such as MAPK and Akt that mediate neuronal development and cell survival. This highlights the role of the serotonergic system in neuroplastic processes known to be altered in MDD and anxiety disorders [3]. Concordant to our results, VBM-studies found a reduction of hippocampal GMV in MDD and a reduction of medial temporal lobe GMV in anxiety disorders. To conclude, our results confirm the role of serotonergic neuronal transmission in cytoarchitectonic processes within regions involved in the modulation of mood and provide an explanatory approach for structural and functional alterations found in MDD and anxiety disorders. References [1] Akimova, E., Lanzenberger, R., Kasper, S., 2009 The serotonin-1A receptor in anxiety disorders. Biological Psychiatry 66, 627−35. [2] Vetencourt, M., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., O’Leary, O.F., Castren E., Mattei, L., 2008 The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385−8. [3] van Tol, M.J., van der Wee, N.J.A., van den Heuvel, O.A., Nielen, M.M.A, Demenescu, L.R., Aleman, A., Renken, R., van Buchem, M.A., Zitman, F.G., Veltman, D.J., 2010 Regional brain volume in depression and anxiety disorders. Archives of General Psychiatry 67, 1002−11.
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P.1.e.028 Resting-state functional connectivity of the raphe nuclei A. Hoeflich1 ° , A. Hahn1 , C. Kraus1 , P. Baldinger1 , G.S. Kranz1 , J. Losak1 , C. Windischberger2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, MR Center of Excellence-Center for Medical Physics and Biomedical Engineering, Vienna, Austria Aim of the study: It is well established that the serotonergic system originating in the raphe nuclei plays a decisive role both in psychiatric disorders such as depression and anxiety disorders and in the therapeutic efficacy of SSRIs. Several fMRI studies have focused on the detection of resting-state networks and lately seven bilateral networks covering 80% of the gray matter volume have been identified and linked to a set of major cortical and subcortical hubs [1]. Since cortical structure and function is influenced by modulatory neurotransmitters such as serotonin the aim of the present study was to investigate resting-state functional connectivity of the dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN) as the main serotonergic nuclei projecting to cortical and subcortical areas. Methods: 29 healthy volunteers (12 men, 17 women, 27.5±7 years) underwent a resting-state functional MR scan at 3 Tesla (Medspec S300 MR 163 Scanner; Bruker Biospin, Germany) lasting for 6 minutes. Analysis of functional connectivity data was performed as previously described [2]. Briefly, preprocessing included motion correction, normalization to MNI space and correction for ventricular, white matter and global signal. DRN and MRN were selected as seed regions based on anatomical studies, computing voxel-wise cross-correlation between seed regions and the entire brain. One sample t-tests were carried out in SPM8 for each seed region separately. To investigate differences between DRN and MRN connectivity a repeated measures ANOVA controlling for sex was performed. All statistical tests were carried out two-tailed with a significance level of p < 0.05, FDR-corrected. Results: Functional connectivity analysis of the DRN revealed a significant association with the anterior cingulate cortex (ACC) (t = 5.52, 4/44/4 mm MNI space) and the thalamus bilaterally (left: t = 5.55, −14/8/2 mm; right: t = 7.24, 14/−4/0 mm) extending into the globus pallidus. Comparably, the MRN showed a significant association to the ACC (t = 3.86, 4/40/−4 mm). Direct comparison between the two seed regions showed significantly higher functional connectivity of the DRN with the precuneus (t = 5.05, 2/−70/48 mm) and the thalamus bilaterally (left: t = 3.82, −16/−18/8 mm, right: t = 4.49, 14/−20/6 mm). No significant differences were attained in the ACC. All reported t-values survived FDR correction. Conclusion: In concordance with preclinical data, the results of this investigation indicate that the raphe nuclei may have a differential modulatory influence on cortical and subcortical areas. Hence, this modulation seems to be area-specific with the DRN being significantly stronger connected to the thalamus and the precuneus, a region which has been lately identified as major cortical hub in the default-mode network [1]. The retrieved results fit well in the context of previous studies emphasizing a reciprocal regulative relationship between frontal brain areas and the raphe nuclei [3] and point toward a modulatory function of the serotonergic system on brain areas implicated in the processing of emotion and cognition such as the ACC and the thalamus. This modulatory influence of DRN and MRN may be altered in affective disorders.