- Email: [email protected]
P.1.e.007 Abnormal cortical neurotransmitter levels in young people at familial risk of depression
S292
P.1.e. Basic and clinical neuroscience − Brain imaging
P.1.e.007 Abnormal cortical neurotransmitter levels in young people at familial risk of depression M.J. Taylor1 ° , Z.N. Mannie1 , R. Norbury1 , J. Near2 , P.J. Cowen1 . 1 University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2 University of Oxford, Centre for Functional Resonance Imaging of the Brain (FMRIB), Oxford, United Kingdom Background: Major depressive disorder is associated with changes in brain chemistry that may be demonstrated using proton Magnetic Resonance Spectroscopy (MRS). In parieto-occipital regions, abnormal levels of neurotransmitters are found during episodes of major depression, with decreased GABA and increased glutamate reported (1). A similar pattern is also found in people who have previously been depressed but have now fully recovered (2). It is unclear whether these differences in GABA and glutamate reflect an underlying trait vulnerability to depression, or are an after-effect (‘scar’) of the episode of illness. To answer this question it is necessary to study people who are vulnerable to depression, but have not yet been depressed. A history of major depression in at least one parent is known to be associated with an elevated risk of developing depression (3). Methods: Young people (ages 16 to 21) with a family history of parental depression (FH+) were compared to a control group without a history of depression in any first-degree relative (FH-). All participants had no personal history of Axis 1 mental disorder (assessed by the Structured Clinical Interview for DSM-IV) and were free of any psychotropic medication. MRS measurements were taken from a 30x30x20 mm voxel in parieto-occipital cortex using a Varian 3 Tesla scanner. Short echo time (26 ms) PRESS, PRESS-J, and MEGA-PRESS acquisitions were obtained to allow quantitation of glutamate, GABA, and Glx (total glutamate + glutamine) relative to creatine as an internal control. Measures of myo-inositol, choline, and N-acetyl aspartate were also obtained from the same spectra. Group differences were tested by multivariate analysis. Results: MRS data were obtained for 24 participants with a family history of parental depression (13 female, 11 male) and 28 participants (14 female, 14 male) without a family history of depression. An effect of group was seen (F(6,43) = 2.6, p = 0.032). FH+ participants had higher levels of glutamate within the voxel (p = 0.02), but did not differ from controls in levels of GABA (p = 0.65) or Glx (p = 0.89) or other MRS measures. Conclusions: These data suggest that increased glutamate levels in parieto-occipital cortex may represent a trait marker of depression vulnerability. By contrast, the lowered GABA levels seen after recovery from major depressive disorder may represent an effect of episodes of illness. Longitudinal studies are required to confirm this interpretation. This study was supported by the Medical Research Council. References [1] Sanacora G, Gueorguieva R, Epperson N et al. 2004 Subtype-specific alterations of g-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713. [2] Bhagwagar Z, Wylezinska M, Jezzard P et al. Reduction in occipital cortex g-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psych 61:806–012. [3] Beardslee WR, Versage EM, Gladstone TR. Children of affectively ill parents: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 37:1134−41.
P.1.e.008 Impact of genetic polymorphism on resting state functional connectivity in healthy subjects M.S. Byun1 ° , W.H. Jung2 , J.H. Jang1 , D.H. Kang1 , S.J. Kwon3 , C.H. Choi4 , J.S. Kwon1 . 1 Seoul National University College of Medicine, Department of Psychiatry, Seoul, South-Korea; 2 Seoul National University, Interdisciplinary Program in Brain Science, Seoul, South-Korea; 3 Seoul National University College of Medicine, Clinical Cognitive Neuroscience Center, Seoul, SouthKorea; 4 National Medical Center, Department of Diagnostic Radiology, Seoul, South-Korea Brain-derived neurotrophic factor (BDNF) val66met polymorphism and catechol-O-methyltransferase (COMT) val158met polymorphism have been reported to affect neuropsychological function and brain structure. Functional imaging studies also revealed that these genetic polymorphisms have linked with activations of several brain regions during the task but there are only few studies about the impact of these genetic variations on the resting state functional connectivity. In this study, we hypothesized that there might be a difference in patterns of resting functional connectivity between BDNF and COMT genetic polymorphisms. To test these hypotheses, we used functional MRI (fMRI) to examine brain activity in a group of 23 healthy right-handed subjects (15 male/8 female; age: 24.13±3.67 years old). The Structured Clinical Interview for DSM-IV Non-patient Version was used to assess all participants to identify past and current psychiatric illnesses. The Korean version of the Wechsler Adult Intelligence Scale (K-WAIS) were also administered to all subjects (mean IQ: 112.96±9.99, mean years of education: 14.43 ±1.38 years). Whole blood was collected for genotyping and BDNF val66met and COMT val158met polymorphisms were detected by TaqMan allelic discrimination assays on ABI Prism 7500 Sequence Detection System. Functional imaging data were acquired using a 1.5-Tesla Avanto scanner while subjects kept their eyes closed during the scan. The posterior cingulate cortex (PCC) was selected as the seed region for the default mode network map and Statistical Parametric Mapping (SPM5) and REST package (REST version 1.3) were used to examine the functional connectivity of the PCC for each subject. According to the genotype, we divided subjects into two groups for each polymorphism: valallele homozygotes (n = 11)/met-allele carriers (n = 12) of BDNF val66met polymorphism and val-allele homozygotes (n = 8)/metallele carriers (n = 15) of COMT val158met polymorphism. A onesample t-test was performed for within-group analysis and a twosample t-test was used to examine the difference in the degree of functional connectivity between two groups. No significant differences of age, sex ratio, IQ and years of education were observed between the two groups of each polymorphism. The one-sample t tests for each group revealed the pattern of the default mode network, including the medial frontal cortex, precuneus, inferior parietal cortex (false discovery rate p < 0.05). Val-allele homozygotes of BDNF val66met polymorphism showed greater activation in the left precuneus compared with met-allele carriers (uncorrected p < 0.0.005). On the other hand, Val-allele homozygotes of COMT val158met polymorphism showed greater activation in the left medial frontal cortex, left and right superior frontal cortex, right cingulate cortex and left cerebellum compared with met-allele carriers of COMT polymorphism (uncorrected p < 0.005). In conclusion, we found that genetic variants in BDNF showed altered resting functional connectivity in the precuneus region
P.1.e. Basic and clinical neuroscience − Brain imaging
P.1.e.007 Abnormal cortical neurotransmitter levels in young people at familial risk of depression M.J. Taylor1 ° , Z.N. Mannie1 , R. Norbury1 , J. Near2 , P.J. Cowen1 . 1 University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2 University of Oxford, Centre for Functional Resonance Imaging of the Brain (FMRIB), Oxford, United Kingdom Background: Major depressive disorder is associated with changes in brain chemistry that may be demonstrated using proton Magnetic Resonance Spectroscopy (MRS). In parieto-occipital regions, abnormal levels of neurotransmitters are found during episodes of major depression, with decreased GABA and increased glutamate reported (1). A similar pattern is also found in people who have previously been depressed but have now fully recovered (2). It is unclear whether these differences in GABA and glutamate reflect an underlying trait vulnerability to depression, or are an after-effect (‘scar’) of the episode of illness. To answer this question it is necessary to study people who are vulnerable to depression, but have not yet been depressed. A history of major depression in at least one parent is known to be associated with an elevated risk of developing depression (3). Methods: Young people (ages 16 to 21) with a family history of parental depression (FH+) were compared to a control group without a history of depression in any first-degree relative (FH-). All participants had no personal history of Axis 1 mental disorder (assessed by the Structured Clinical Interview for DSM-IV) and were free of any psychotropic medication. MRS measurements were taken from a 30x30x20 mm voxel in parieto-occipital cortex using a Varian 3 Tesla scanner. Short echo time (26 ms) PRESS, PRESS-J, and MEGA-PRESS acquisitions were obtained to allow quantitation of glutamate, GABA, and Glx (total glutamate + glutamine) relative to creatine as an internal control. Measures of myo-inositol, choline, and N-acetyl aspartate were also obtained from the same spectra. Group differences were tested by multivariate analysis. Results: MRS data were obtained for 24 participants with a family history of parental depression (13 female, 11 male) and 28 participants (14 female, 14 male) without a family history of depression. An effect of group was seen (F(6,43) = 2.6, p = 0.032). FH+ participants had higher levels of glutamate within the voxel (p = 0.02), but did not differ from controls in levels of GABA (p = 0.65) or Glx (p = 0.89) or other MRS measures. Conclusions: These data suggest that increased glutamate levels in parieto-occipital cortex may represent a trait marker of depression vulnerability. By contrast, the lowered GABA levels seen after recovery from major depressive disorder may represent an effect of episodes of illness. Longitudinal studies are required to confirm this interpretation. This study was supported by the Medical Research Council. References [1] Sanacora G, Gueorguieva R, Epperson N et al. 2004 Subtype-specific alterations of g-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713. [2] Bhagwagar Z, Wylezinska M, Jezzard P et al. Reduction in occipital cortex g-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psych 61:806–012. [3] Beardslee WR, Versage EM, Gladstone TR. Children of affectively ill parents: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 37:1134−41.
P.1.e.008 Impact of genetic polymorphism on resting state functional connectivity in healthy subjects M.S. Byun1 ° , W.H. Jung2 , J.H. Jang1 , D.H. Kang1 , S.J. Kwon3 , C.H. Choi4 , J.S. Kwon1 . 1 Seoul National University College of Medicine, Department of Psychiatry, Seoul, South-Korea; 2 Seoul National University, Interdisciplinary Program in Brain Science, Seoul, South-Korea; 3 Seoul National University College of Medicine, Clinical Cognitive Neuroscience Center, Seoul, SouthKorea; 4 National Medical Center, Department of Diagnostic Radiology, Seoul, South-Korea Brain-derived neurotrophic factor (BDNF) val66met polymorphism and catechol-O-methyltransferase (COMT) val158met polymorphism have been reported to affect neuropsychological function and brain structure. Functional imaging studies also revealed that these genetic polymorphisms have linked with activations of several brain regions during the task but there are only few studies about the impact of these genetic variations on the resting state functional connectivity. In this study, we hypothesized that there might be a difference in patterns of resting functional connectivity between BDNF and COMT genetic polymorphisms. To test these hypotheses, we used functional MRI (fMRI) to examine brain activity in a group of 23 healthy right-handed subjects (15 male/8 female; age: 24.13±3.67 years old). The Structured Clinical Interview for DSM-IV Non-patient Version was used to assess all participants to identify past and current psychiatric illnesses. The Korean version of the Wechsler Adult Intelligence Scale (K-WAIS) were also administered to all subjects (mean IQ: 112.96±9.99, mean years of education: 14.43 ±1.38 years). Whole blood was collected for genotyping and BDNF val66met and COMT val158met polymorphisms were detected by TaqMan allelic discrimination assays on ABI Prism 7500 Sequence Detection System. Functional imaging data were acquired using a 1.5-Tesla Avanto scanner while subjects kept their eyes closed during the scan. The posterior cingulate cortex (PCC) was selected as the seed region for the default mode network map and Statistical Parametric Mapping (SPM5) and REST package (REST version 1.3) were used to examine the functional connectivity of the PCC for each subject. According to the genotype, we divided subjects into two groups for each polymorphism: valallele homozygotes (n = 11)/met-allele carriers (n = 12) of BDNF val66met polymorphism and val-allele homozygotes (n = 8)/metallele carriers (n = 15) of COMT val158met polymorphism. A onesample t-test was performed for within-group analysis and a twosample t-test was used to examine the difference in the degree of functional connectivity between two groups. No significant differences of age, sex ratio, IQ and years of education were observed between the two groups of each polymorphism. The one-sample t tests for each group revealed the pattern of the default mode network, including the medial frontal cortex, precuneus, inferior parietal cortex (false discovery rate p < 0.05). Val-allele homozygotes of BDNF val66met polymorphism showed greater activation in the left precuneus compared with met-allele carriers (uncorrected p < 0.0.005). On the other hand, Val-allele homozygotes of COMT val158met polymorphism showed greater activation in the left medial frontal cortex, left and right superior frontal cortex, right cingulate cortex and left cerebellum compared with met-allele carriers of COMT polymorphism (uncorrected p < 0.005). In conclusion, we found that genetic variants in BDNF showed altered resting functional connectivity in the precuneus region