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

  • Gemma Modinos (a1) (a2), Alice Egerton (a1), Anna McLaughlin (a1), Katrina McMullen (a2), Veena Kumari (a3), David J. Lythgoe (a2), Gareth J. Barker (a2), André Aleman (a4) and Steve C. R. Williams (a2)...

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.

Copyright

Corresponding author

Author for correspondence: Gemma Modinos, E-mail: gemma.modinos@kcl.ac.uk

References

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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.
Adler, CM, Levine, AD, DelBello, MP and Strakowski, SM (2005) Changes in gray matter volume in patients with bipolar disorder. Biological Psychiatry 58, 151157.
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.
Ashburner, J (2010) VBM tutorial. Available at http://www.fil.ion.ucl.ac.uk/~john/misc/VBMclass10.pdf.
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.
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.
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.
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.
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.
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.
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.
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.
Cavanna, AE and Trimble, MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129, 564583.
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.
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.
Choi, DW (1994) Calcium and excitotoxic neuronal injury. Annals of the New York Academy of Sciences 747, 162171.
Cochrane, M, Petch, I and Pickering, AD (2010) Do measures of schizotypal personality provide non-clinical analogues of schizophrenic symptomatology? Psychiatry Research 176, 150154.
Deutsch, SI, Rosse, RB, Schwartz, BL and Mastropaolo, J (2001) A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clinical Neuropharmacology 24, 4349.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lodge, DJ and Grace, AA (2011) Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends in Pharmacological Sciences 32, 507513.
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.
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.
Mason, O, Linney, Y and Claridge, G (2005) Short scales for measuring schizotypy. Schizophrenia Research 78, 293296.
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.
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.
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.
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.
Modenato, C and Draganski, B (2015) The concept of schizotypy – a computational anatomy perspective. Schizophrenia Research: Cognition 2, 8992.
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.
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.
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.
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.
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.
Pantelis, C and Bartholomeusz, CF (2014) Social neuroscience in psychiatry: pathways to discovering neurobiological risk and resilience. World Psychiatry 13, 146147.
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.
Port, JD and Agarwal, N (2011) MR spectroscopy in schizophrenia. Journal of Magnetic Resonance Imaging 34, 12511261.
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.
Provencher, SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine 30, 672679.
Provencher S. LCModel & LCMgui User's Manual (2016) http://s-provencher.com/pub/LCModel/manual/manual.pdf.
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.
Raine, A (1991) The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17, 555564.
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.
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.
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.
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.
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.
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.
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.
Utevsky, AV, Smith, DV and Huettel, SA (2014) Precuneus is a functional core of the default-mode network. The Journal of Neuroscience 34, 932940.
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.
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.
Wiebels, K, Waldie, KE, Roberts, RP and Park, HR (2016) Identifying grey matter changes in schizotypy using partial least squares correlation. Cortex 81, 137150.

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