Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: Relationship to IQ and early trauma
Abstract
We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.
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A decrease in choline and creatine levels is found in the left hippocampus and centrum semiovale in human adults with anxiety disorder.
“A decrease in choline and creatine levels is also found in the left hippocampus and centrum semiovale in human adults with anxiety disorder [101, 102].”
From Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy (2024) · cites this paper as [101]
Cites
Childhood trauma associated with smaller hippocampal volume in women with major depression
Vythilingam, M., Heim, C., Newport, J., Miller, A. H., Anderson, E., Bronen, R., Brummer, M., Staib, L., Vermetten, E., Charney, D. S., et al. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.12.2072 · Cited by 812 · see citing works
Kreis, R., Ernst, T., & Ross, B. D. (1993) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910300405 · Cited by 680 · see citing works
Hamilton, M. (1980) · PubMed · Cited by 471 · see citing works
Brain Metabolic Alterations in Medication-Free Patients With BipolarDisorder
Dager, S. R., Friedman, S. D., Parow, A. M., Demopulos, C. M., Stoll, A. L., Lyoo, I. K., Dünner, D. L., & Renshaw, P. F. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.5.450 · Cited by 453 · see citing works
Kendler, K. S., Davis, C. G., & Kessler, R. C. (1997) · British Journal of Psychiatry · doi:10.1192/bjp.170.6.541 · Cited by 412 · see citing works
Prefrontal white matter volume is disproportionately larger in humans than in other primates
Schoenemann, P. T., Sheehan, M. J., & Glotzer, L. D. (2005) · Nature Neuroscience · doi:10.1038/nn1394 · Cited by 405 · see citing works
Behar, E., Alcaine, O., Zuellig, A. R., & Borkovec, T. D. (2003) · Journal of Behavior Therapy and Experimental Psychiatry · doi:10.1016/s0005-7916(03)00004-1 · Cited by 373 · see citing works
Psychometric properties of the STAI: A reply to Ramanaiah, Franzen, and Schill
Speilberger, C. D., & Vagg, P. R. (1984) · Journal of Personality Assessment · doi:10.1207/s15327752jpa4801_16 · Cited by 355 · see citing works
Multisection proton MR spectroscopic imaging of the brain.
Duyn, J. H., GILLEN, J. S., Sobering, G., van Zijl, P. C. M., & MOONEN, C. T. W. (1993) · Radiology · doi:10.1148/radiology.188.1.8511313 · Cited by 353 · see citing works
Clinical applications of proton MR spectroscopy.
Castillo, M., Kwock, L., & Mukherji, S. K. (1996) · PubMed · Cited by 352 · see citing works
The epidemiology of generalized anxiety disorder
Kessler, R. C., Keller, M. B., & Wittchen, H.-U. (2001) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(05)70204-5 · Cited by 337 · see citing works
Pharmacotherapy of Social Phobia
Versiani, M., Nardi, A. E., Mundim, F. D., Alves, A. B., Liebowitz, M. R., & Amrein, R. (1992) · The British Journal of Psychiatry · doi:10.1192/bjp.161.3.353 · Cited by 333 · see citing works
Quantitative proton MR spectroscopic imaging of the human brain
Soher, B. J., van Zijl, P. C. M., Duyn, J. H., & Barker, P. B. (1996) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910350313 · Cited by 271 · see citing works
MICHAEL, N., Erfurth, A., Ohrmann, P., Arolt, V., Heindel, W. L., & Pfleiderer, B. (2003) · Psychological Medicine · doi:10.1017/s0033291703007931 · Cited by 260 · see citing works
Sullivan, G., Coplan, J., Kent, J., & Gorman, J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00246-2 · Cited by 245 · see citing works
Self-citationAnimal intelligence as encephalization
Jerison, H. J. (1985) · Philosophical Transactions of the Royal Society of London. B, Biological Sciences · doi:10.1098/rstb.1985.0007 · Cited by 234 · see citing works
Vulnerability factors among children at risk for anxiety disorders
Merikangas, K. R., Avenevoli, S., Dierker, L., & Grillon, C. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00172-9 · Cited by 229 · see citing works
PET in generalized anxiety disorder
Wu, J. C., Buchsbaum, M. S., Hershey, T. G., Hazlett, E. A., Sicotte, N. L., & Johnson, J. C. (1991) · Biological Psychiatry · doi:10.1016/0006-3223(91)90326-h · Cited by 205 · see citing works
Steingard, R. J., Yurgelun-Todd, D. A., Hennen, J. A., Moore, J. C., Moore, C. M., Vakili, K., Young, A. D., Katic, A., Beardslee, W. R., & Renshaw, P. F. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(00)00942-2 · Cited by 144 · see citing works
Biochemical markers of intelligence: a proton MR spectroscopy study of normal human brain
Jung, R. E., Brooks, W. M., Yeo, R. A., Chiulli, S. J., Weers, D. C., & Sibbitt, W. L. (1999) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1999.0790 · Cited by 140 · see citing works
Murphy, D., Critchley, H., Schmitz, N., McAlonan, G. M., van Amelsvoort, T., Robertson, D., Daly, E., Rowe, A., Russell, A., Simmons, A., et al. (2002) · Archives of General Psychiatry · doi:10.1001/archpsyc.59.10.885 · Cited by 140 · see citing works
Risk factors for suicide attempts among African American women
Kaslow, N., Thompson, M. P., Meadows, L. A., Chance, S., Puett, R., Hollins, L., Jessee, S., & Kellermann, A. (2000) · Depression and Anxiety · doi:10.1002/1520-6394(2000)12:1 · Cited by 129 · see citing works
Generalized anxiety disorder: comorbidity, comparative biology and treatment
Nutt, D., Ballenger, J. C., Sheehan, D. V., & Wïttchen, H. (2002) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145702003048 · Cited by 122 · see citing works
Hays, J. R., Reas, D. L., & Shaw, J. B. (2002) · Psychological Reports · doi:10.2466/pr0.2002.90.2.355 · Cited by 116 · see citing works
Jung, R. E., Haier, R. J., Yeo, R. A., Rowland, L. M., Petropoulos, H., Levine, A. S., Sibbitt, W. L., & Brooks, W. M. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2005.02.039 · Cited by 114 · see citing works
Magnetic resonance spectroscopy: current and future applications in psychiatric research
Lyoo, I. K., & Renshaw, P. F. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01313-0 · Cited by 104 · see citing works
31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis
Yıldız, A., Sachs, G. S., Dorer, D. J., et al. (2001) · Psychiatry Research Neuroimaging · doi:10.1016/s0925-4927(01)00082-8 · Cited by 89 · see citing works
Anxiety in healthy humans is associated with orbital frontal chemistry
Grachev, I. D., & Apkarian, A. V. (2000) · Molecular Psychiatry · doi:10.1038/sj.mp.4000778 · Cited by 81 · see citing works
Mathew, S. J., Mao, X., Coplan, J. D., Smith, E. L., Sackeïm, H. A., Gorman, J. M., & Shungu, D. C. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.6.1119 · Cited by 79 · see citing works
Self-citationValenzuela, M., Sachdev, P. S., Wen, W., Shnier, R. C., Brodaty, H., & Gillies, D. (2000) · NeuroImage · doi:10.1006/nimg.2000.0629 · Cited by 76 · see citing works
Pfleiderer, B., Ohrmann, P., Suslow, T., et al. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.11.008 · Cited by 67 · see citing works
Keshavan, M. S., Kapur, S., & Pettegrew, J. W. (1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.8.976 · Cited by 67 · see citing works
Russell, A., Cortese, B., Lorch, E., Ivey, J., Banerjee, S. P., Moore, G. J., & Rosenberg, D. R. (2003) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/104454603322126322 · Cited by 63 · cited 1× · see citing works
“MRSI studies also provide new evidence of localized functional neurochemical marker alterations in left DLPFC in pediatric OCD (Russell et al., 2003).”
BackgroundFayed, N. M., & Modrego, P. J. (2005) · Academic Radiology · doi:10.1016/j.acra.2005.01.016 · Cited by 54 · see citing works
DAWSON, R. M. C., Hemington, N., & Irvine, R. F. (1985) · Biochemical Journal · doi:10.1042/bj2300061 · Cited by 44 · see citing works
Cognitive correlates of 1H MRS measures in the healthy elderly brain
Ross, A. J., Sachdev, P. S., Wen, W. X., Valenzuela, M., & Brodaty, H. (2005) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2005.01.015 · Cited by 42 · see citing works
Massana, G., Gastó, C., Junqué, C., Mercader, J. M., Gómez‐Ansón, B., Massana, J., Torres, X., & Salamero, M. (2002) · NeuroImage · doi:10.1006/nimg.2002.1083 · Cited by 41 · see citing works
On the relationship between manifest anxiety and intelligence.
Spielberger, C. D. (1958) · Journal of Consulting Psychology · doi:10.1037/h0044773 · Cited by 38 · see citing works
The development of clonazepam as a psychotropic: the massachusetts general hospital experience.
Rosenbaum, J. F. (2004) · PubMed · Cited by 29 · see citing works
Pearlson, G. D., Rabins, P. V., & Burns, A. S. (1991) · Psychological Medicine · doi:10.1017/s0033291700020420 · Cited by 29 · see citing works
Tedeschi, G., Righini, A., Bizzi, A., et al. (1995) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910330120 · Cited by 28 · see citing works
Public health perspectives on generalized anxiety disorder.
Stein, M. B. (2004) · PubMed · Cited by 26 · see citing works
New Challenges for Anxiety Disorders: Where Treatment, Resilience, and Economic Priority Converge
Pollack, M. H., Stein, M. B., Davidson, J. R. T., & Ginsberg, D. L. (2004) · CNS Spectrums · doi:10.1017/s1092852900027097 · Cited by 25 · see citing works
Pharmacotherapy of social phobia.
Domenici, N., & Griffin-Francell, C. (1993) · PubMed · Cited by 20 · see citing works
Hays, J. R. (2002) · Psychological Reports · doi:10.2466/pr0.90.2.355-359 · Cited by 17 · see citing works
[Gifted children and dysharmonious development].
Catheline-Antipoff, N., & Poinso, F. (1994) · PubMed · Cited by 9 · see citing works
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High intelligence: A risk factor for psychological and physiological overexcitabilities
Karpinski, R. I., Kinase Kolb, A. M., Tetreault, N. A., & Borowski, T. B. (2018) · Intelligence · doi:10.1016/j.intell.2017.09.001 · Cited by 217 · see citing works
Wu, Y., Lu, Y.-C., Jacobs, M., Pradhan, S., Kapse, K., Zhao, L., Niforatos-Andescavage, N., Vezina, G., du Plessis, A. J., & Limperopoulos, C. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.19940 · Cited by 218 · see citing works
Exploring the therapeutic role of creatine supplementation
Gualano, B., Artioli, G. G., Poortmans, J. R., & Lancha Junior, A. H. (2010) · Amino Acids · doi:10.1007/s00726-009-0263-6 · Cited by 156 · see citing works
Wu, Y., De Asis-Cruz, J., & Limperopoulos, C. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02449-0 · Cited by 124 · see citing works
“A decrease in choline and creatine levels is also found in the left hippocampus and centrum semiovale in human adults with anxiety disorder [101, 102].”
BackgroundCreatine supplementation in fibromyalgia: A randomized, double-blind, placebo-controlled trial
Alves, C. R. R., Santiago, B. M., Lima, F. R., Otaduy, M. C. G., Calich, A. L., Tritto, A. C. C., de Sá Pinto, A. L., Roschel, H., Leite, C. C., Benatti, F. B., et al. (2013) · Arthritis Care & Research · doi:10.1002/acr.22020 · Cited by 73 · see citing works
Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight
Coplan, J. D., Fathy, H. M., Abdallah, C. G., Ragab, S. A., Kral, J. G., Mao, X., Shungu, D. C., & Mathew, S. J. (2014) · NeuroImage: Clinical · doi:10.1016/j.nicl.2013.12.014 · Cited by 28 · see citing works
Self-citation
- Authors
- Coplan, J. D., Mathew, S. J., Mao, X., Smith, E. L. P., Hof, P. R., Coplan, P. M., Rosenblum, L. A., Gorman, J. M., & Shungu, D. C.
- Affiliations
- State University of New York (US)
- Icahn School of Medicine at Mount Sinai (US)
- Cornell University (US)
- International Partnership for Microbicides (US)
- Corresponding author
- Coplan, Jeremy D.
- ORCID
- Venue
- Psychiatry Research: Neuroimaging
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 147
- Issue
- 1
- Pages
- 27-39
- ISSN
- 0925-4927 (ISSN-L)
- OpenAlex
- W2054154633
- Cited by
- 45
- References
- 46
- Citations by year
- 2025: 5 · 2024: 1 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 1 · 2012: 5
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychiatry Research Neuroimaging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (K23MH069656, T32MH15144, T32MH015144)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- generalized anxiety disorder, centrum semiovale, choline, creatine, N-acetylaspartate, white matter, early trauma, intelligence, worry, dorsolateral prefrontal cortex, proton magnetic resonance spectroscopic imaging, metabolite concentrations, Penn State Worry Questionnaire, WASI
- MeSH terms
- Adult, Anxiety Disorders, Choline, Cognition Disorders, Creatine, Frontal Lobe, Humans, Functional Laterality, Magnetic Resonance Spectroscopy, Phosphocreatine, Protons, Surveys and Questionnaires, Regression Analysis, Stress Disorders, Post-Traumatic, Time Factors, Wechsler Scales, Body Mass Index, Prosencephalon
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