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P.1.029 Multimodal neuroimaging with PET and MRI to investigate the relation between serotonergic neurotransmission and regional brain volumes
S28
Molecular neuropsychopharmacology
P.1.029 Multimodal neuroimaging with PET and MRI to investigate the relation between serotonergic neurotransmission and regional brain volumes C. Kraus1 ° , M. Savli1 , A. Hahn1 , A. H¨oflich1 , P. Baldinger1 , W. Wadsak2 , C. Windischberger3 , C. Mitterhauser2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, Nuclear Medicine, Vienna, Austria; 3 Medical University of Vienna, Center for Medical Physics and Biomedical Engineering, Vienna, Austria Purpose of the study: Altered neuroplasticity is consistently reported to be involved in the neuropathophysiology of major depressive disorder, schizophrenia and Alzheimer’s disease. Morphometric methods using structural magnetic resonance imaging (MRI) and voxelbased morphometry (VBM) demonstrated losses of gray matter volume, whereby the hippocampus and other brain areas of the limbic system proved to be especially vulnerable [1]. Furthermore, growing evidence shows distinctive neuromodulatory properties of serotonin (5-hydroxytryptamine, 5-HT) in developing and mature brain networks [2]. The major inhibitory serotonergic (5-HT1A ) receptor directly mediates neuroplasticity and was also demonstrated to be quantitatively altered in vivo by positron emission tomography (PET) in patients with depression, schizophrenia and Alzheimer’s disease [3]. In this study we examined the neuroplastic properties of 5-HT1A receptors in vivo using structural MRI and PET in healthy subjects. Methods: PET using the 5-HT1A -receptor-specific radioligand [carbonyl-11 C]WAY-100635 and structural high-field MRI were performed in 35 healthy subjects (mean 26.6±6.8 years; 17 women) to quantify voxel-wise 5-HT1A receptor binding (5-HT1A BPND ), associated with 5-HT1A receptor density, and gray matter volume (GMV), respectively. To demonstrate associations between 5-HT1A receptor BPND and GMV multiple linear regression was calculated with GMV as dependent and 5-HT1A BPND as independent variable. Additionally, to evaluate a potential regulatory influence of the major serotonergic nucleus, the dorsal raphe nucleus (DRN), we calculated regression analysis between whole brain GMV as dependent variable and 5-HT1A BPND of the DRN as independent variable. Control variables in both analyses were age, sex and total GMV. Finally, an independent ROI-approach using an anatomical atlas was used to confirm the results. Results: 5-HT1A receptor binding was highly significantly associated with GMV in the hippocampus, medial
temporal cortex, inferior temporal cortex, medial occipital cortex and the pericalcarine region in each hemisphere (R2 : 0.308–0.503, p < 0.05 false discovery rate corrected). ROI-based analysis further suggested significant positive associations in the hippocampus, but not in the insula, a selected control region with similar GMV values and a similar GMV/receptor BPND ratio as the hippocampus. This suggests that these associations do not dependent on the absolute value of local gray matter volumes. Finally, 5-HT1A receptor levels in the DRN were associated with GMV of the anterior cingulate cortex (R2 = 0.656, p = 0.001, uncorrected). Conclusions: Our results demonstrate that 5-HT1A receptor-mediated neuroplasticity is detectable in vivo in healthy human subjects. These associations occur regionally in distinctive areas, symmetrically in the brain, but they were not associated with locally higher values of GMV. Moreover the DRN, previously known to regulate tonic serotonergic firing as well as 5-HT1A receptor densities throughout the brain, was discovered to regulate GMV of the medial forebrain. These results show that a combination of structural and molecular neuroimaging might be able to reveal dysfunctional neuroregulatory processes, which could lead to gray matter atrophy in clinical populations. This approach could provide a better understanding of neuropsychiatric disorders such as Alzheimer’s disease, schizophrenia and mood disorders and ultimately a better diagnostic assessment and therapeutic evaluation of patients with these highly life impairing disorders. Reference(s) [1] Macqueen, G. & Frodl, T, (2010), The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry, Mar;16(3), 252−64. [2] Daubert, E.A. & Condron, B.G., (2010), Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33, 424–434. [3] Savitz, J., Lucki, I. & Drevets, W.C. (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88, 17−31.
Molecular neuropsychopharmacology
P.1.029 Multimodal neuroimaging with PET and MRI to investigate the relation between serotonergic neurotransmission and regional brain volumes C. Kraus1 ° , M. Savli1 , A. Hahn1 , A. H¨oflich1 , P. Baldinger1 , W. Wadsak2 , C. Windischberger3 , C. Mitterhauser2 , S. Kasper1 , R. Lanzenberger1 . 1 Medical University of Vienna, Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, Nuclear Medicine, Vienna, Austria; 3 Medical University of Vienna, Center for Medical Physics and Biomedical Engineering, Vienna, Austria Purpose of the study: Altered neuroplasticity is consistently reported to be involved in the neuropathophysiology of major depressive disorder, schizophrenia and Alzheimer’s disease. Morphometric methods using structural magnetic resonance imaging (MRI) and voxelbased morphometry (VBM) demonstrated losses of gray matter volume, whereby the hippocampus and other brain areas of the limbic system proved to be especially vulnerable [1]. Furthermore, growing evidence shows distinctive neuromodulatory properties of serotonin (5-hydroxytryptamine, 5-HT) in developing and mature brain networks [2]. The major inhibitory serotonergic (5-HT1A ) receptor directly mediates neuroplasticity and was also demonstrated to be quantitatively altered in vivo by positron emission tomography (PET) in patients with depression, schizophrenia and Alzheimer’s disease [3]. In this study we examined the neuroplastic properties of 5-HT1A receptors in vivo using structural MRI and PET in healthy subjects. Methods: PET using the 5-HT1A -receptor-specific radioligand [carbonyl-11 C]WAY-100635 and structural high-field MRI were performed in 35 healthy subjects (mean 26.6±6.8 years; 17 women) to quantify voxel-wise 5-HT1A receptor binding (5-HT1A BPND ), associated with 5-HT1A receptor density, and gray matter volume (GMV), respectively. To demonstrate associations between 5-HT1A receptor BPND and GMV multiple linear regression was calculated with GMV as dependent and 5-HT1A BPND as independent variable. Additionally, to evaluate a potential regulatory influence of the major serotonergic nucleus, the dorsal raphe nucleus (DRN), we calculated regression analysis between whole brain GMV as dependent variable and 5-HT1A BPND of the DRN as independent variable. Control variables in both analyses were age, sex and total GMV. Finally, an independent ROI-approach using an anatomical atlas was used to confirm the results. Results: 5-HT1A receptor binding was highly significantly associated with GMV in the hippocampus, medial
temporal cortex, inferior temporal cortex, medial occipital cortex and the pericalcarine region in each hemisphere (R2 : 0.308–0.503, p < 0.05 false discovery rate corrected). ROI-based analysis further suggested significant positive associations in the hippocampus, but not in the insula, a selected control region with similar GMV values and a similar GMV/receptor BPND ratio as the hippocampus. This suggests that these associations do not dependent on the absolute value of local gray matter volumes. Finally, 5-HT1A receptor levels in the DRN were associated with GMV of the anterior cingulate cortex (R2 = 0.656, p = 0.001, uncorrected). Conclusions: Our results demonstrate that 5-HT1A receptor-mediated neuroplasticity is detectable in vivo in healthy human subjects. These associations occur regionally in distinctive areas, symmetrically in the brain, but they were not associated with locally higher values of GMV. Moreover the DRN, previously known to regulate tonic serotonergic firing as well as 5-HT1A receptor densities throughout the brain, was discovered to regulate GMV of the medial forebrain. These results show that a combination of structural and molecular neuroimaging might be able to reveal dysfunctional neuroregulatory processes, which could lead to gray matter atrophy in clinical populations. This approach could provide a better understanding of neuropsychiatric disorders such as Alzheimer’s disease, schizophrenia and mood disorders and ultimately a better diagnostic assessment and therapeutic evaluation of patients with these highly life impairing disorders. Reference(s) [1] Macqueen, G. & Frodl, T, (2010), The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry, Mar;16(3), 252−64. [2] Daubert, E.A. & Condron, B.G., (2010), Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33, 424–434. [3] Savitz, J., Lucki, I. & Drevets, W.C. (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88, 17−31.