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P.3.22 Serotonin1A receptor distribution may predict neural reactivity as shown by multimodal neuroimaging with fMRI and PET
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Clinical neuropsychopharmacology
P.3.21 Delta-9-tetrahydrocannabinol modulates activity in parahippocampal cortex and ventral striatum during memory processing S. Bhattacharyya1 ° , P. Fusar-Poli1 , S. Borgwardt1 , P. Allen1 , R. Martin-Santos1 , C. O’Carroll1 , M. Seal1 , Z. Atakan1 , P.K. McGuire1 . 1 Institute of Psychiatry, Section of Neuroimaging, London, United Kingdom Background: Cannabis is the world’s most widely used illicit drug. It can impair various cognitive functions, particularly verbal learning and induce psychosis, both acutely and possibly following long term use [1,2]. But, where cannabis acts in the brain to impair verbal learning and induce psychotic symptoms is unclear. The aim of this study was to clarify how one of the main psychoactive ingredients of cannabis, delta-9tetrahydrocannabinol (THC) acts on the brain to impair verbal learning and induce psychotic symptoms. Methods: 15 healthy males, who had minimal exposure to cannabis in lifetime, were studied on 2 occasions approximately 1 month apart, following oral administration of 10 mg of delta-9-Tetrahydrocannabinol (THC) or placebo 1 hour prior to scanning, in a double-blind design. MR images were acquired on a 1.5T GE camera while subjects performed a Verbal paired associates task with separate encoding followed by retrieval conditions, with the conditions repeated in the same sequence 4 times. Image acquisition was compressed during the task to permit processing of auditory-verbal stimuli in silence. Task responses were recorded on-line. Symptomatic responses (anxiety, intoxication, sedation and psychotic symptoms) were assessed at regular intervals. We examined the main effect of drug, main effect of task and drug–task interactions. Results: During the verbal paired associates task, repeated presentation of word pairs during encoding was associated with a progressive improvement in word recall and a linear decrement in the engagement of the parahippocampal gyrus bilaterally, which directly correlated with verbal learning occurring over repeated trials as indexed by recall score. Administration of THC abolished the change in parahippocampal activation across successive encoding blocks and was associated with a trend for impaired word recall. During the recall condition, over repeated trials, progressive improvement in word recall was normally associated with a progressive decrease in engagement of the middle frontal gyrus on the left side. Greater the magnitude of the change in middle frontal activation, greater was the improvement in recall score. This decremental pattern of middle frontal
activation over repeated recall trials was disrupted by THC. Administration of THC also altered the normal time-dependent change in ventral striatal activation during retrieval of word pairs which was directly correlated with concurrently induced psychotic symptoms. Conclusions: Our results are consistent with the central role played by the parahippocampal cortex in verbal learning and evidence of THC-induced impairment of hippocampal function in animals and memory function in humans [1,3]. Association between effect of THC on ventral striatal activation and concurrently induced psychotic symptoms is consistent with its effect on altering dopamine levels in this area in animals [2]. These results suggest that impairment in learning and verbal memory associated with cannabis use may be mediated through its action in the medial temporal cortex while psychotic symptoms may be induced through its action in the ventral striatum. Reference(s) [1] Ranganathan M, D’Souza DC, 2006, The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology Berlin 188, 425−44. [2] Murray RM, Morrison PD, Henquet C, Di Forti M, 2007, Cannabis, the mind and society: the hash realities. Nat Rev Neurosci 8(11), 885−95. [3] Robbe D, Montgomery SM, Thome A, RuedaOrozco PE, McNaughton BL, Buzsaki G, 2006, Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 9(12), 1526−33. P.3.22 Serotonin1A receptor distribution may predict neural reactivity as shown by multimodal neuroimaging with fMRI and PET M. Fink1 ° , R. Lanzenberger1 , M. Mitterhauser2 , C. Windischberger3 , P. Stein1 , C. Spindelegger1 , W. Wadsak2 , U. Moser1 , K. Kletter2 , S. Kasper1 . 1 Medical University of Vienna, Department of Psychiatry, Vienna, Austria; 2 Medical University of Vienna, Department of Nuclear Medicine, Vienna, Austria; 3 Medical University of Vienna, Centre for Biomedical Engineering and Physics, Vienna, Austria Background: The major inhibitory serotonin receptor 5-HT1A inhibits long-term potentiation (LTP) by suppression of glutamatergic function and induces postsynaptic hyperpolarisation. This indicates an important function of the serotonin1A (5-HT1A) receptor in area-specific regulation of neural (re)activity as well as plasticity, memory and learning (Edagawa et al. 1999). Here, we
Clinical neuropsychopharmacology investigated the relation between the 5-HT1A receptor binding measured by positron emission tomography (PET) and the task-specific neural activation in limbic and visual areas measured by functional magnetic resonance imaging (fMRI) based on the BOLD-effect. Methods: We included 30 healthy subjects (25.0±4.5y, 12 males) and performed measurements with both PET (30 frames, 90 min, 4.4 mm FWHM, 35 slices) and fMRI. 5-HT1A receptor binding potential (BP) was quantified by administering the radioligand [carbonyl-11 C]WAY-100635 and using the SRTM with the cerebellum as reference region. The fMRI scan (3 T, EPI inplane 1.6×2.7 mm, 10 AC-PC orientated slices, ST 3 mm, TE/TR = 31/1000 ms) included two paradigms to obtain task-specific neuronal activation. Subjects performed an emotion discrimination task (EDT, comparison of faces expressing different emotions) for limbic activation (Fisher et al. 2006) and a sensorimotor control task (SMCT, matching geometrical objects) for activation of visual areas. Subject-specific parameter estimates calculated using SPM2 were extracted from limbic (amygdala) and visual (V1) ROIs. Regional 5-HT1A receptor BP of 8 ROIs were correlated with BOLD parameter estimates of the contrast between the emotion discrimination and control task using Pearson‘s correlation analysis (two-tailed, p < 0.00625 threshold for multiple comparison). Results: Statistical analyses showed a negative correlation between neural reactivity in the visual cortex and the regional 5-HT1A receptor BP obtained from the orbitofrontal cortex (r = −0.61, p = 0.0003), anterior cingulate (r = −0.51, p = 0.004), and retrosplenial cortices (r = −0.50, p = 0.005), amygdala (r = −0.46, p = 0.0098), insula (r = −0.46, p = 0.010), and posterior cingulate cortex (r = −0.43, p = 0.017), but not in the hippocampus or raphe nuclei (p > 0.05). There was no significant correlation between neural activity in the amygdala and regional 5-HT1A receptor BPs. Conculsion: The highly significant negative correlation between neural activation and 5-HT1A receptor BP in several areas is consistent to the inhibitory function of 5-HT1A receptors on glutamatergic neurons, the major excitatory neurons in the brain. This mechanism might be relevant in the pathogenesis and treatment of depression, anxiety disorders and schizophrenia showing altered 5-HT1A receptor levels (Lanzenberger et al. 2007). Reference(s) [1] Edagawa Y, Saito H, Abe K, 1999, Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex. Brain Res 827(1−2), 225–228. [2] Fisher PM, Meltzer CC, Ziolko SK, Price JC, MosesKolko EL, Berga SL, Hariri AR, 2006, Capacity for
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5-HT1A-mediated autoregulation predicts amygdala reactivity. Nat Neurosci 9(11), 1362–1363. [3] Lanzenberger RR, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien LK, Holik A, Attarbaschi T, Mossaheb N, Sacher J, Geiss-Granadia T, Kletter K, Kasper S, Tauscher J, 2007, Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 61(9), 1081–1089.
P.3.23 Molecular imaging of early visual cortex by combining pet and fMRI F. Gerstl1 ° , C. Windischberger1 , E. Moser1 , S. Kasper2 , R. Lanzenberger2 . 1 Medical University of Vienna, Institute for Biomedical Engineering and Physics MR Centre of Excellence, Vienna, Austria; 2 Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria Introduction: Although there are numerous studies using either PET or fMRI, there is considerable lack of studies combining both modalities to investigate the relationship between neuroreceptor distribution patterns and functional organization of the human brain. This relationship, however, seems to be the key factor for understanding the processes underlying neuropsychiatric symptoms. For the serotonergic system, the major inhibitory receptor 5-HT1A shows a distinct topological distribution. Primary sensory areas express very low levels of the 5-HT1A receptor compared to adjacent cortical regions [1]. Here we assessed the relationship of neurochemical cortical borders as determined by PET with the functional organization of the primary visual cortex as indicated by fMRI retinotopy by overlaying parametric receptor distribution maps on structural data. Methods: A group of 7 young, healthy subjects participated in this study. In order to compare neuroreceptor and functional distribution patterns, all subjects underwent both PET and fMRI measurements. Quantitative data of the 5-HT1A receptor was acquired using a GE Advance PET scanner and the radioligand [carbonyl-11 C]WAY-100635. The parametric distribution of the 5-HT1A receptor was calculated using the SRTM and PMOD2.7. Functional imaging was performed at 3 Tesla (Bruker Biospin, Germany). Subjects performed a visual stimulation paradigm involving the presentation of two opposing checkerboard-wedges in a “propeller” configuration. This stimulus activation allowed for activation mapping specific to the polar properties of the visual. The usual fMRI preprocessing steps were performed with SPM5. A cortical surface model was constructed from the structural MR scans and flattened
Clinical neuropsychopharmacology
P.3.21 Delta-9-tetrahydrocannabinol modulates activity in parahippocampal cortex and ventral striatum during memory processing S. Bhattacharyya1 ° , P. Fusar-Poli1 , S. Borgwardt1 , P. Allen1 , R. Martin-Santos1 , C. O’Carroll1 , M. Seal1 , Z. Atakan1 , P.K. McGuire1 . 1 Institute of Psychiatry, Section of Neuroimaging, London, United Kingdom Background: Cannabis is the world’s most widely used illicit drug. It can impair various cognitive functions, particularly verbal learning and induce psychosis, both acutely and possibly following long term use [1,2]. But, where cannabis acts in the brain to impair verbal learning and induce psychotic symptoms is unclear. The aim of this study was to clarify how one of the main psychoactive ingredients of cannabis, delta-9tetrahydrocannabinol (THC) acts on the brain to impair verbal learning and induce psychotic symptoms. Methods: 15 healthy males, who had minimal exposure to cannabis in lifetime, were studied on 2 occasions approximately 1 month apart, following oral administration of 10 mg of delta-9-Tetrahydrocannabinol (THC) or placebo 1 hour prior to scanning, in a double-blind design. MR images were acquired on a 1.5T GE camera while subjects performed a Verbal paired associates task with separate encoding followed by retrieval conditions, with the conditions repeated in the same sequence 4 times. Image acquisition was compressed during the task to permit processing of auditory-verbal stimuli in silence. Task responses were recorded on-line. Symptomatic responses (anxiety, intoxication, sedation and psychotic symptoms) were assessed at regular intervals. We examined the main effect of drug, main effect of task and drug–task interactions. Results: During the verbal paired associates task, repeated presentation of word pairs during encoding was associated with a progressive improvement in word recall and a linear decrement in the engagement of the parahippocampal gyrus bilaterally, which directly correlated with verbal learning occurring over repeated trials as indexed by recall score. Administration of THC abolished the change in parahippocampal activation across successive encoding blocks and was associated with a trend for impaired word recall. During the recall condition, over repeated trials, progressive improvement in word recall was normally associated with a progressive decrease in engagement of the middle frontal gyrus on the left side. Greater the magnitude of the change in middle frontal activation, greater was the improvement in recall score. This decremental pattern of middle frontal
activation over repeated recall trials was disrupted by THC. Administration of THC also altered the normal time-dependent change in ventral striatal activation during retrieval of word pairs which was directly correlated with concurrently induced psychotic symptoms. Conclusions: Our results are consistent with the central role played by the parahippocampal cortex in verbal learning and evidence of THC-induced impairment of hippocampal function in animals and memory function in humans [1,3]. Association between effect of THC on ventral striatal activation and concurrently induced psychotic symptoms is consistent with its effect on altering dopamine levels in this area in animals [2]. These results suggest that impairment in learning and verbal memory associated with cannabis use may be mediated through its action in the medial temporal cortex while psychotic symptoms may be induced through its action in the ventral striatum. Reference(s) [1] Ranganathan M, D’Souza DC, 2006, The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology Berlin 188, 425−44. [2] Murray RM, Morrison PD, Henquet C, Di Forti M, 2007, Cannabis, the mind and society: the hash realities. Nat Rev Neurosci 8(11), 885−95. [3] Robbe D, Montgomery SM, Thome A, RuedaOrozco PE, McNaughton BL, Buzsaki G, 2006, Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 9(12), 1526−33. P.3.22 Serotonin1A receptor distribution may predict neural reactivity as shown by multimodal neuroimaging with fMRI and PET M. Fink1 ° , R. Lanzenberger1 , M. Mitterhauser2 , C. Windischberger3 , P. Stein1 , C. Spindelegger1 , W. Wadsak2 , U. Moser1 , K. Kletter2 , S. Kasper1 . 1 Medical University of Vienna, Department of Psychiatry, Vienna, Austria; 2 Medical University of Vienna, Department of Nuclear Medicine, Vienna, Austria; 3 Medical University of Vienna, Centre for Biomedical Engineering and Physics, Vienna, Austria Background: The major inhibitory serotonin receptor 5-HT1A inhibits long-term potentiation (LTP) by suppression of glutamatergic function and induces postsynaptic hyperpolarisation. This indicates an important function of the serotonin1A (5-HT1A) receptor in area-specific regulation of neural (re)activity as well as plasticity, memory and learning (Edagawa et al. 1999). Here, we
Clinical neuropsychopharmacology investigated the relation between the 5-HT1A receptor binding measured by positron emission tomography (PET) and the task-specific neural activation in limbic and visual areas measured by functional magnetic resonance imaging (fMRI) based on the BOLD-effect. Methods: We included 30 healthy subjects (25.0±4.5y, 12 males) and performed measurements with both PET (30 frames, 90 min, 4.4 mm FWHM, 35 slices) and fMRI. 5-HT1A receptor binding potential (BP) was quantified by administering the radioligand [carbonyl-11 C]WAY-100635 and using the SRTM with the cerebellum as reference region. The fMRI scan (3 T, EPI inplane 1.6×2.7 mm, 10 AC-PC orientated slices, ST 3 mm, TE/TR = 31/1000 ms) included two paradigms to obtain task-specific neuronal activation. Subjects performed an emotion discrimination task (EDT, comparison of faces expressing different emotions) for limbic activation (Fisher et al. 2006) and a sensorimotor control task (SMCT, matching geometrical objects) for activation of visual areas. Subject-specific parameter estimates calculated using SPM2 were extracted from limbic (amygdala) and visual (V1) ROIs. Regional 5-HT1A receptor BP of 8 ROIs were correlated with BOLD parameter estimates of the contrast between the emotion discrimination and control task using Pearson‘s correlation analysis (two-tailed, p < 0.00625 threshold for multiple comparison). Results: Statistical analyses showed a negative correlation between neural reactivity in the visual cortex and the regional 5-HT1A receptor BP obtained from the orbitofrontal cortex (r = −0.61, p = 0.0003), anterior cingulate (r = −0.51, p = 0.004), and retrosplenial cortices (r = −0.50, p = 0.005), amygdala (r = −0.46, p = 0.0098), insula (r = −0.46, p = 0.010), and posterior cingulate cortex (r = −0.43, p = 0.017), but not in the hippocampus or raphe nuclei (p > 0.05). There was no significant correlation between neural activity in the amygdala and regional 5-HT1A receptor BPs. Conculsion: The highly significant negative correlation between neural activation and 5-HT1A receptor BP in several areas is consistent to the inhibitory function of 5-HT1A receptors on glutamatergic neurons, the major excitatory neurons in the brain. This mechanism might be relevant in the pathogenesis and treatment of depression, anxiety disorders and schizophrenia showing altered 5-HT1A receptor levels (Lanzenberger et al. 2007). Reference(s) [1] Edagawa Y, Saito H, Abe K, 1999, Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex. Brain Res 827(1−2), 225–228. [2] Fisher PM, Meltzer CC, Ziolko SK, Price JC, MosesKolko EL, Berga SL, Hariri AR, 2006, Capacity for
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5-HT1A-mediated autoregulation predicts amygdala reactivity. Nat Neurosci 9(11), 1362–1363. [3] Lanzenberger RR, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien LK, Holik A, Attarbaschi T, Mossaheb N, Sacher J, Geiss-Granadia T, Kletter K, Kasper S, Tauscher J, 2007, Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 61(9), 1081–1089.
P.3.23 Molecular imaging of early visual cortex by combining pet and fMRI F. Gerstl1 ° , C. Windischberger1 , E. Moser1 , S. Kasper2 , R. Lanzenberger2 . 1 Medical University of Vienna, Institute for Biomedical Engineering and Physics MR Centre of Excellence, Vienna, Austria; 2 Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria Introduction: Although there are numerous studies using either PET or fMRI, there is considerable lack of studies combining both modalities to investigate the relationship between neuroreceptor distribution patterns and functional organization of the human brain. This relationship, however, seems to be the key factor for understanding the processes underlying neuropsychiatric symptoms. For the serotonergic system, the major inhibitory receptor 5-HT1A shows a distinct topological distribution. Primary sensory areas express very low levels of the 5-HT1A receptor compared to adjacent cortical regions [1]. Here we assessed the relationship of neurochemical cortical borders as determined by PET with the functional organization of the primary visual cortex as indicated by fMRI retinotopy by overlaying parametric receptor distribution maps on structural data. Methods: A group of 7 young, healthy subjects participated in this study. In order to compare neuroreceptor and functional distribution patterns, all subjects underwent both PET and fMRI measurements. Quantitative data of the 5-HT1A receptor was acquired using a GE Advance PET scanner and the radioligand [carbonyl-11 C]WAY-100635. The parametric distribution of the 5-HT1A receptor was calculated using the SRTM and PMOD2.7. Functional imaging was performed at 3 Tesla (Bruker Biospin, Germany). Subjects performed a visual stimulation paradigm involving the presentation of two opposing checkerboard-wedges in a “propeller” configuration. This stimulus activation allowed for activation mapping specific to the polar properties of the visual. The usual fMRI preprocessing steps were performed with SPM5. A cortical surface model was constructed from the structural MR scans and flattened