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Neuroanatomical changes in people with high schizotypy: relationship to glutamate levels

Published online by Cambridge University Press:  04 December 2017

Gemma Modinos*
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Alice Egerton
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Anna McLaughlin
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Katrina McMullen
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Veena Kumari
Affiliation:
Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
David J. Lythgoe
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Gareth J. Barker
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
André Aleman
Affiliation:
Department of Neuroscience, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
Steve C. R. Williams
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
*
Author for correspondence: Gemma Modinos, E-mail: gemma.modinos@kcl.ac.uk

Abstract

Background

Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels.

Methods

We selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry.

Results

Subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (pFWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (pFWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (pFWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (pFWE = 0.026). Such association was absent in LS.

Conclusions

Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2017 

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References

Abbott, C and Bustillo, J (2006) What have we learned from proton magnetic resonance spectroscopy about schizophrenia? A critical update. Current Opinion in Psychiatry 19, 135139.Google Scholar
Adler, CM, Levine, AD, DelBello, MP and Strakowski, SM (2005) Changes in gray matter volume in patients with bipolar disorder. Biological Psychiatry 58, 151157.Google Scholar
Aoyama, N, Theberge, J, Drost, DJ, Manchanda, R, Northcott, S, Neufeld, RW, Menon, RS, Rajakumar, N, Pavlosky, WF, Densmore, M, Schaefer, B and Williamson, PC (2011) Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. The British Journal of Psychiatry 198, 448456.Google Scholar
Ashburner, J (2010) VBM tutorial. Available at http://www.fil.ion.ucl.ac.uk/~john/misc/VBMclass10.pdf.Google Scholar
Barrantes-Vidal, N, Grant, P and Kwapil, TR (2015) The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders. Schizophrenia Bulletin 41(suppl. 2), S408S416.Google Scholar
Berretta, S, Munno, DW and Benes, FM (2001) Amygdalar activation alters the hippocampal GABA system: partial modelling for postmortem changes in schizophrenia. Journal of Comparative Neurology 431, 129138.Google Scholar
Boos, HB, Aleman, A, Cahn, W, Hulshoff Pol, H and Kahn, RS (2007) Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Archives of General Psychiatry 64, 297304.Google Scholar
Bora, E, Fornito, A, Radua, J, Walterfang, M, Seal, M, Wood, SJ, Yucel, M, Velakoulis, D and Pantelis, C (2011) Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophrenia Research 127, 4657.Google Scholar
Borgwardt, SJ, McGuire, P, Fusar-Poli, P, Radue, EW and Riecher-Rossler, A (2008) Anterior cingulate pathology in the prodromal stage of schizophrenia. NeuroImage 39, 553554.Google Scholar
Borgwardt, SJ, McGuire, PK, Aston, J, Berger, G, Dazzan, P, Gschwandtner, U, Pfluger, M, D'Souza, M, Radue, EW and Riecher-Rossler, A (2007 a) Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis. The British Journal of Psychiatry 51, S69S75.Google Scholar
Borgwardt, SJ, Riecher-Rossler, A, Dazzan, P, Chitnis, X, Aston, J, Drewe, M, Gschwandtner, U, Haller, S, Pfluger, M, Rechsteiner, E, D'Souza, M, Stieglitz, RD, Radu, EW and McGuire, PK (2007 b). Regional gray matter volume abnormalities in the at risk mental state. Biological Psychiatry 61, 11481156.Google Scholar
Cannon, TD, Chung, Y, He, G, Sun, D, Jacobson, A, van Erp, TG, McEwen, S, Addington, J, Bearden, CE, Cadenhead, K, Cornblatt, B, Mathalon, DH, McGlashan, T, Perkins, D, Jeffries, C, Seidman, LJ, Tsuang, M, Walker, E, Woods, SW, Heinssen, R and North American Prodrome Longitudinal Study C (2015) Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biological Psychiatry 77, 147157.Google Scholar
Cavanna, AE and Trimble, MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129, 564583.Google Scholar
Chan, RC, Di, X, McAlonan, GM and Gong, QY (2011) Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: an activation likelihood estimation meta-analysis of illness progression. Schizophrenia Bulletin 37, 177188.Google Scholar
Chen, QL, Xu, T, Yang, WJ, Li, YD, Sun, JZ, Wang, KC, Beaty, RE, Zhang, QL, Zuo, XN and Qiu, J (2015) Individual differences in verbal creative thinking are reflected in the precuneus. Neuropsychologia 75, 441449.Google Scholar
Choi, DW (1994) Calcium and excitotoxic neuronal injury. Annals of the New York Academy of Sciences 747, 162171.Google Scholar
Cochrane, M, Petch, I and Pickering, AD (2010) Do measures of schizotypal personality provide non-clinical analogues of schizophrenic symptomatology? Psychiatry Research 176, 150154.Google Scholar
Deutsch, SI, Rosse, RB, Schwartz, BL and Mastropaolo, J (2001) A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clinical Neuropharmacology 24, 4349.Google Scholar
Egerton, A, Bhachu, A, Merritt, K, McQueen, G, Szulc, A and McGuire, P (2017) Effects of antipsychotic administration on brain glutamate in schizophrenia: a systematic review of longitudinal 1H-MRS studies. Frontiers in Psychiatry 8.Google Scholar
Egerton, A, Brugger, S, Raffin, M, Barker, GJ, Lythgoe, DJ, McGuire, PK and Stone, JM (2012) Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 37, 25152521.Google Scholar
Egerton, A, Stone, JM, Chaddock, CA, Barker, GJ, Bonoldi, I, Howard, RM, Merritt, K, Allen, P, Howes, OD, Murray, RM, McLean, MA, Lythgoe, DJ, O'Gorman, RL and McGuire, PK (2014) Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis. Neuropsychopharmacology 39, 28912899.Google Scholar
Ettinger, U, Williams, SC, Meisenzahl, EM, Moller, HJ, Kumari, V and Koutsouleris, N (2012) Association between brain structure and psychometric schizotypy in healthy individuals. The World Journal of Biological Psychiatry 13, 544549.Google Scholar
Fusar-Poli, P, Borgwardt, S, Crescini, A, Deste, G, Kempton, MJ, Lawrie, S, Mc Guire, P and Sacchetti, E (2011) Neuroanatomy of vulnerability to psychosis: a voxel-based meta-analysis. Neuroscience & Biobehavioral Reviews 35, 11751185.Google Scholar
Gomes, FV, Rincon-Cortes, M and Grace, AA (2016) Adolescence as a period of vulnerability and intervention in schizophrenia: insights from the MAM model. Neuroscience & Biobehavioral Reviews 70, 260270.Google Scholar
Haijma, SV, Van Haren, N, Cahn, W, Koolschijn, PC, Hulshoff Pol, HE and Kahn, RS (2013) Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophrenia Bulletin 39, 11291138.Google Scholar
Honea, R, Crow, TJ, Passingham, D and Mackay, CE (2005) Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. The American Journal of Psychiatry 162, 22332245.Google Scholar
Kraguljac, NV, White, DM, Reid, MA and Lahti, AC (2013) Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. JAMA Psychiatry 70, 12941302.Google Scholar
Kwapil, TR, Gross, GM, Silvia, PJ and Barrantes-Vidal, N (2013) Prediction of psychopathology and functional impairment by positive and negative schizotypy in the Chapmans’ ten-year longitudinal study. Journal of Abnormal Psychology 122, 807815.Google Scholar
Liemburg, E, Sibeijn-Kuiper, A, Bais, L, Pijnenborg, G, Knegtering, H, van der Velde, J, Opmeer, E, de Vos, A, Dlabac-De Lange, J, Wunderink, L. and Aleman, A (2016) Prefrontal NAA and Glx levels in different stages of psychotic disorders: a 3 T 1H-MRS study. Scientific Reports 6, 21873.Google Scholar
Linscott, RJ and van Os, J (2013) An updated and conservative systematic review and meta-analysis of epidemiological evidence on psychotic experiences in children and adults: on the pathway from proneness to persistence to dimensional expression across mental disorders. Psychological Medicine 43, 11331149.Google Scholar
Lodge, DJ and Grace, AA (2011) Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends in Pharmacological Sciences 32, 507513.Google Scholar
Marsman, A, van den Heuvel, MP, Klomp, DW, Kahn, RS, Luijten, PR and Hulshoff Pol, HE (2013) Glutamate in schizophrenia: a focused review and meta-analysis of (1)H-MRS studies. Schizophrenia Bulletin 39, 120129.Google Scholar
Mason, O and Claridge, G (2006) The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE): further description and extended norms. Schizophrenia Research 82, 203211.Google Scholar
Mason, O, Linney, Y and Claridge, G (2005) Short scales for measuring schizotypy. Schizophrenia Research 78, 293296.Google Scholar
McDonald, C, Dineen, B and Hallahan, B (2008) Meta-analysis of brain volumes in unaffected first-degree relatives of patients with schizophrenia overemphasizes hippocampal deficits. Archives of General Psychiatry 65, 603604; author reply 604–5.Google Scholar
Mechelli, A, Riecher-Rossler, A, Meisenzahl, EM, Tognin, S, Wood, SJ, Borgwardt, SJ, Koutsouleris, N, Yung, AR, Stone, JM, Phillips, LJ, McGorry, PD, Valli, I, Velakoulis, D, Woolley, J, Pantelis, C and McGuire, P (2011) Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. Archives of General Psychiatry 68, 489495.Google Scholar
Merritt, K, Egerton, A, Kempton, MJ, Taylor, MJ and McGuire, PK (2016) Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73, 665674.Google Scholar
Miller, L, Bansal, R, Wickramaratne, P, Hao, X, Tenke, CE, Weissman, MM and Peterson, BS (2014) Neuroanatomical correlates of religiosity and spirituality: a study in adults at high and low familial risk for depression. JAMA Psychiatry 71, 128135.Google Scholar
Modenato, C and Draganski, B (2015) The concept of schizotypy – a computational anatomy perspective. Schizophrenia Research: Cognition 2, 8992.Google Scholar
Modinos, G, McLaughlin, A, Egerton, A, McMullen, K, Kumari, V, Barker, GJ, Keysers, C and Williams, SC (2017) Corticolimbic hyper-response to emotion and glutamatergic function in people with high schizotypy: a multimodal fMRI-MRS study. Translational Psychiatry 7, e1083.Google Scholar
Modinos, G, Mechelli, A, Ormel, J, Groenewold, NA, Aleman, A and McGuire, PK (2010) Schizotypy and brain structure: a voxel-based morphometry study. Psychological Medicine 40, 14231431.Google Scholar
Mouchlianitis, E, Bloomfield, MA, Law, V, Beck, K, Selvaraj, S, Rasquinha, N, Waldman, A, Turkheimer, FE, Egerton, A, Stone, J and Howes, OD (2016) Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophrenia Bulletin 42, 744752.Google Scholar
Nelson, MT, Seal, ML, Pantelis, C and Phillips, LJ (2013) Evidence of a dimensional relationship between schizotypy and schizophrenia: a systematic review. Neuroscience & Biobehavioral Reviews 37, 317327.Google Scholar
Nenadic, I, Lorenz, C, Langbein, K, Dietzek, M, Smesny, S, Schonfeld, N, Fananas, L, Sauer, H and Gaser, C (2015) Brain structural correlates of schizotypy and psychosis proneness in a non-clinical healthy volunteer sample. Schizophrenia Research 168, 3743.Google Scholar
Pantelis, C and Bartholomeusz, CF (2014) Social neuroscience in psychiatry: pathways to discovering neurobiological risk and resilience. World Psychiatry 13, 146147.Google Scholar
Plitman, E, Patel, R, Chung, JK, Pipitone, J, Chavez, S, Reyes-Madrigal, F, Gomez-Cruz, G, Leon-Ortiz, P, Chakravarty, MM, de la Fuente-Sandoval, C and Graff-Guerrero, A (2016) Glutamatergic metabolites, volume and cortical thickness in antipsychotic-naive patients with first-episode psychosis: implications for excitotoxicity. Neuropsychopharmacology 41, 26062613.Google Scholar
Port, JD and Agarwal, N (2011) MR spectroscopy in schizophrenia. Journal of Magnetic Resonance Imaging 34, 12511261.Google Scholar
Premkumar, P, Ettinger, U, Inchley-Mort, S, Sumich, A, Williams, SC, Kuipers, E and Kumari, V (2012) Neural processing of social rejection: the role of schizotypal personality traits. Human Brain Mapping 33, 695706.Google Scholar
Provencher, SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine 30, 672679.Google Scholar
Provencher S. LCModel & LCMgui User's Manual (2016) http://s-provencher.com/pub/LCModel/manual/manual.pdf.Google Scholar
Radua, J, Borgwardt, S, Crescini, A, Mataix-Cols, D, Meyer-Lindenberg, A, McGuire, PK and Fusar-Poli, P (2012) Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience & Biobehavioral Reviews 36, 23252333.Google Scholar
Raine, A (1991) The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17, 555564.Google Scholar
Satterthwaite, TD, Wolf, DH, Calkins, ME, Vandekar, SN, Erus, G, Ruparel, K, Roalf, DR, Linn, KA, Elliott, MA, Moore, TM, Hakonarson, H, Shinohara, RT, Davatzikos, C, Gur, RC and Gur, RE (2016) Structural brain abnormalities in youth With psychosis spectrum symptoms. JAMA Psychiatry 73, 515524.Google Scholar
Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, Hergueta, T, Baker, R and Dunbar, GC (1998) The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59(suppl. 20), 2233; quiz 34–57.Google Scholar
Snyder, J and Wilman, A (2010) Field strength dependence of PRESS timings for simultaneous detection of glutamate and glutamine from 1.5 to 7 T. Journal of Magnetic Resonance 203, 6672.Google Scholar
Stone, JM, Day, F, Tsagaraki, H, Valli, I, McLean, MA, Lythgoe, DJ, O'Gorman, RL, Barker, GJ, McGuire, PK on Behalf of OASIS (2009) Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biological Psychiatry 66, 533539.Google Scholar
Teicher, MH, Samson, JA, Anderson, CM and Ohashi, K (2016) The effects of childhood maltreatment on brain structure, function and connectivity. Nature Reviews Neuroscience 17, 652666.Google Scholar
Theberge, J, Williamson, KE, Aoyama, N, Drost, DJ, Manchanda, R, Malla, AK, Northcott, S, Menon, RS, Neufeld, RW, Rajakumar, N, Pavlosky, W, Densmore, M, Schaefer, B and Williamson, PC (2007) Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. The British Journal of Psychiatry 191, 325334.Google Scholar
Tyrer, P, Nur, U, Crawford, M, Karlsen, S, McLean, C, Rao, B and Johnson, T (2005) The social functioning questionnaire: a rapid and robust measure of perceived functioning. International Journal of Social Psychiatry 51, 265275.Google Scholar
Utevsky, AV, Smith, DV and Huettel, SA (2014) Precuneus is a functional core of the default-mode network. The Journal of Neuroscience 34, 932940.Google Scholar
Velthorst, E, Levine, SZ, Henquet, C, de Haan, L, van Os, J, Myin-Germeys, I and Reichenberg, A (2013) To cut a short test even shorter: reliability and validity of a brief assessment of intellectual ability in schizophrenia – a control-case family study. Cognitive Neuropsychiatry 18, 574593.Google Scholar
Wang, Y, Yan, C, Yin, DZ, Fan, MX, Cheung, EF, Pantelis, C and Chan, RC (2015) Neurobiological changes of schizotypy: evidence from both volume-based morphometric analysis and resting-state functional connectivity. Schizophrenia Bulletin 41(suppl. 2), S444S454.Google Scholar
Wiebels, K, Waldie, KE, Roberts, RP and Park, HR (2016) Identifying grey matter changes in schizotypy using partial least squares correlation. Cortex 81, 137150.Google Scholar