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Evidence that hippocampal–parahippocampal dysfunction is related to genetic risk for schizophrenia

  • A. Di Giorgio (a1), B. Gelao (a2), G. Caforio (a2), R. Romano (a2), I. Andriola (a2), E. D'Ambrosio (a2), A. Papazacharias (a2), F. Elifani (a2), L. Lo Bianco (a2) (a3), P. Taurisano (a2), L. Fazio (a2), T. Popolizio (a1), G. Blasi (a2) and A. Bertolino (a1) (a2)...

Abstract

Background

Abnormalities in hippocampal–parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state.

Method

We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects.

Results

Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects.

Conclusions

Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype.

Copyright

Corresponding author

*Address for correspondence: A. Bertolino, M.D., Ph.D., Dipartimento di Neuroscienze ed Organi di Senso, Università degli Studi di Bari ‘Aldo Moro’, Piazza Giulio Cesare, 11, 70124, Bari, Italy. (Email: alessandro.bertolino@psichiat.uniba.it)

References

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Achim, AM, Bertrand, MC, Sutton, H, Montoya, A, Czechowska, Y, Malla, AK, Joober, R, Pruessner, JC, Lepage, M (2007). Selective abnormal modulation of hippocampal activity during memory formation in first-episode psychosis. Archives of General Psychiatry 64, 9991014.
Achim, AM, Lepage, M (2005). Episodic memory-related activation in schizophrenia: meta-analysis. British Journal of Psychiatry 187, 500509.
Aleman, A, Hijman, R, de Haan, EH, Kahn, RS (1999). Memory impairment in schizophrenia: a meta-analysis. American Journal of Psychiatry 156, 13581366.
Allen, P, Chaddock, CA, Howes, OD, Egerton, A, Seal, ML, Fusar-Poli, P, Valli, I, Day, F, McGuire, PK (2012). Abnormal relationship between medial temporal lobe and subcortical dopamine function in people with an ultra high risk for psychosis. Schizophrenia Bulletin 38, 10401049.
Allen, P, Seal, ML, Valli, I, Fusar-Poli, P, Perlini, C, Day, F, Wood, SJ, Williams, SC, McGuire, PK (2011). Altered prefrontal and hippocampal function during verbal encoding and recognition in people with prodromal symptoms of psychosis. Schizophrenia Bulletin 37, 746756.
Bertolino, A, Di Giorgio, A, Blasi, G, Sambataro, F, Caforio, G, Sinibaldi, L, Latorre, V, Rampino, A, Taurisano, P, Fazio, L, Romano, R, Douzgou, S, Popolizio, T, Kolachana, B, Nardini, M, Weinberger, DR, Dallapiccola, B (2008). Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks. Biological Psychiatry 64, 226234.
Bertolino, A, Rubino, V, Sambataro, F, Blasi, G, Latorre, V, Fazio, L, Caforio, G, Petruzzella, V, Kolachana, B, Hariri, A, Meyer-Lindenberg, A, Nardini, M, Weinberger, DR, Scarabino, T (2006). Prefrontal-hippocampal coupling during memory processing is modulated by COMT Val158Met genotype. Biological Psychiatry 60, 12501258.
Bigos, KL, Mattay, VS, Callicott, JH, Straub, RE, Vakkalanka, R, Kolachana, B, Hyde, TM, Lipska, BK, Kleinman, JE, Weinberger, DR (2010). Genetic variation in CACNA1C affects brain circuitries related to mental illness. Archives of General Psychiatry 67, 939945.
Bonner-Jackson, A, Csernansky, JG, Barch, DM (2007). Levels-of-processing effects in first-degree relatives of individuals with schizophrenia. Biological Psychiatry 61, 11411147.
Callicott, JH, Egan, MF, Bertolino, A, Mattay, VS, Langheim, FJ, Frank, JA, Weinberger, DR (1998). Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype. Biological Psychiatry 44, 941950.
Callicott, JH, Straub, RE, Pezawas, L, Egan, MF, Mattay, VS, Hariri, AR, Verchinski, BA, Meyer-Lindenberg, A, Balkissoon, R, Kolachana, BS, Goldberg, TE, Weinberger, DR (2005). Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proceedings of the National Academy of Sciences USA 102, 86278632.
Cannon, TD, Zorrilla, LE, Shtasel, D, Gur, RE, Gur, RC, Marco, EJ, Moberg, P, Price, RA (1994). Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. Archives of General Psychiatry 51, 651661.
Danion, JM, Huron, C, Vidailhet, P, Berna, F (2007). Functional mechanisms of episodic memory impairment in schizophrenia. Canadian Journal of Psychiatry 52, 693701.
Di Giorgio, A, Blasi, G, Sambataro, F, Rampino, A, Papazacharias, A, Gambi, F, Romano, R, Caforio, G, Rizzo, M, Latorre, V, Popolizio, T, Kolachana, B, Callicott, JH, Nardini, M, Weinberger, DR, Bertolino, A (2008). Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. European Journal of Neuroscience 28, 21292136.
Di Giorgio, A, Caforio, G, Blasi, G, Taurisano, P, Fazio, L, Romano, R, Ursini, G, Gelao, B, Lo Bianco, L, Papazacharias, A, Sinibaldi, L, Popolizio, T, Bellomo, A, Bertolino, A (2011). Catechol-O-methyltransferase Val158Met association with parahippocampal physiology during memory encoding in schizophrenia. Psychological Medicine 41, 17211731.
Di Giorgio, A, Sambataro, F, Bertolino, A (2009). Functional imaging as a tool to investigate the relationship between genetic variation and response to treatment with antipsychotics. Current Pharmaceutical Design 15, 25602572.
Egan, MF, Kojima, M, Callicott, JH, Goldberg, TE, Kolachana, BS, Bertolino, A, Zaitsev, E, Gold, B, Goldman, D, Dean, M, Lu, B, Weinberger, DR (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257269.
Egan, MF, Straub, RE, Goldberg, TE, Yakub, I, Callicott, JH, Hariri, AR, Mattay, VS, Bertolino, A, Hyde, TM, Shannon-Weickert, C, Akil, M, Crook, J, Vakkalanka, RK, Balkissoon, R, Gibbs, RA, Kleinman, JE, Weinberger, DR (2004). Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proceedings of the National Academy of Sciences USA 101, 1260412609.
Faraone, SV, Seidman, LJ, Kremen, WS, Pepple, JR, Lyons, MJ, Tsuang, MT (1995). Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. Journal of Abnormal Psychology 104, 286304.
Faraone, SV, Seidman, LJ, Kremen, WS, Toomey, R, Pepple, JR, Tsuang, MT (1999). Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study. Journal of Abnormal Psychology 108, 176181.
Faraone, SV, Seidman, LJ, Kremen, WS, Toomey, R, Pepple, JR, Tsuang, MT (2000). Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biological Psychiatry 48, 120126.
First, MB, Gibbon, M, Spitzer, RL, Williams, JBW (1996). Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders – Research Version. Biometrics Research Department, New York State Psychiatric Institute: New York.
Freedman, R, Leonard, S, Olincy, A, Kaufmann, CA, Malaspina, D, Cloninger, CR, Svrakic, D, Faraone, SV, Tsuang, MT (2001). Evidence for the multigenic inheritance of schizophrenia. American Journal of Medical Genetics 105, 794800.
Friston, K (2003). Introduction: Experimental design and statistical parametric mapping. In Human Brain Function (ed. Frackowiak, R., Friston, K., Frith, C., Dolan, R., Friston, K., Price, C., Zeki, S., Ashburner, J. and Penny, W.), pp. 167. Academic Press: London.
Gold, JM (2004). Cognitive deficits as treatment targets in schizophrenia. Schizophrenia Research 72, 2128.
Goldberg, T, David, A, Gold, J (2011). Neurocognitive impairments in schizophrenia: their character and role in symptom formation. In Schizophrenia, 3rd edn (ed. Weinberger, D. and Harrison, P.), pp. 142162. Wiley-Blackwell: Chichester, UK.
Goldberg, TE, Egan, MF, Gscheidle, T, Coppola, R, Weickert, T, Kolachana, BS, Goldman, D, Weinberger, DR (2003). Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Archives of General Psychiatry 60, 889896.
Goldberg, TE, Straub, RE, Callicott, JH, Hariri, A, Mattay, VS, Bigelow, L, Coppola, R, Egan, MF, Weinberger, DR (2006). The G72/G30 gene complex and cognitive abnormalities in schizophrenia. Neuropsychopharmacology 31, 20222032.
Green, MF (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry 153, 321330.
Gur, RE, Calkins, ME, Gur, RC, Horan, WP, Nuechterlein, KH, Seidman, LJ, Stone, WS (2007). The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophrenia Bulletin 33, 4968.
Hariri, AR, Goldberg, TE, Mattay, VS, Kolachana, BS, Callicott, JH, Egan, MF, Weinberger, DR (2003). Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. Journal of Neuroscience 23, 66906694.
Harrison, P, Lewis, D (2003). Neuropathology of schizophrenia. In Schizophrenia (ed. Hirsch, S. and Weinberger, D.), pp. 310325. Blackwell Science: Oxford.
Honea, R, Crow, TJ, Passingham, D, Mackay, CE (2005). Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. American Journal of Psychiatry 162, 22332245.
Huffaker, SJ, Chen, J, Nicodemus, KK, Sambataro, F, Yang, F, Mattay, V, Lipska, BK, Hyde, TM, Song, J, Rujescu, D, Giegling, I, Mayilyan, K, Proust, MJ, Soghoyan, A, Caforio, G, Callicott, JH, Bertolino, A, Meyer-Lindenberg, A, Chang, J, Ji, Y, Egan, MF, Goldberg, TE, Kleinman, JE, Lu, B, Weinberger, DR (2009). A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Medicine 15, 509518.
Karnik-Henry, MS, Wang, L, Barch, DM, Harms, MP, Campanella, C, Csernansky, JG (2012). Medial temporal lobe structure and cognition in individuals with schizophrenia and in their non-psychotic siblings. Schizophrenia Research 138, 128135.
Kay, SR, Fiszbein, A, Opler, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Keshavan, MS, Dick, E, Mankowski, I, Harenski, K, Montrose, DM, Diwadkar, V, DeBellis, M (2002). Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia. Schizophrenia Research 58, 173183.
Kopald, BE, Mirra, KM, Egan, MF, Weinberger, DR, Goldberg, TE (2012). Magnitude of impact of executive functioning and IQ on episodic memory in schizophrenia. Biological Psychiatry 71, 545551.
Krach, S, Jansen, A, Krug, A, Markov, V, Thimm, M, Sheldrick, AJ, Eggermann, T, Zerres, K, Stocker, T, Shah, NJ, Kircher, T (2010). COMT genotype and its role on hippocampal-prefrontal regions in declarative memory. NeuroImage 53, 978984.
Krug, A, Markov, V, Krach, S, Jansen, A, Zerres, K, Eggermann, T, Stocker, T, Shah, NJ, Nothen, MM, Treutlein, J, Rietschel, M, Kircher, T (2010). The effect of Neuregulin 1 on neural correlates of episodic memory encoding and retrieval. NeuroImage 53, 985991.
Jansen, A, Krach, S, Krug, A, Markov, V, Thimm, M, Paulus, FM, Zerres, K, Stocker, T, Shah, NJ, Nothen, MM, Treutlein, J, Rietschel, M, Kircher, T (2010). The effect of G72 genotype on neural correlates of memory encoding and retrieval. NeuroImage 53, 10011006.
Lang, PJ, Bradley, MM, Cuthbert, BN (1997). International Affective Picture System (IAPS): Technical Manual and Affective Ratings. NIMH Center for the Study of Emotion and Attention, University of Florida: Gainesville, FL.
Leavitt, VM, Goldberg, TE (2009). Episodic memory in schizophrenia. Neuropsychology Review 19, 312323.
Lepage, M, Sergerie, K, Pelletier, M, Harvey, PO (2007). Episodic memory bias and the symptoms of schizophrenia. Canadian Journal of Psychiatry 52, 702709.
Lipska, BK, Weinberger, DR (2000). To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23, 223229.
MacDonald, AW 3rd, Thermenos, HW, Barch, DM, Seidman, LJ (2009). Imaging genetic liability to schizophrenia: systematic review of FMRI studies of patients' nonpsychotic relatives. Schizophrenia Bulletin 35, 11421162.
Maxwell, M (1992). Family Interview for Genetic Studies (FIGS): Manual For FIGS. Clinical Neurogenetics Branch, Intramural Research Program, National Institute of Mental Health: Bethesda, MD.
Nelson, D (1979). Remembering pictures and words: appearance, significance and name. In Levels of Processing in Human Memory (ed. Cermak, L. and Craik, F.), pp. 4576. Lawrence Erlbaum: Hillsdale, NJ.
O'Driscoll, GA, Florencio, PS, Gagnon, D, Wolff, AV, Benkelfat, C, Mikula, L, Lal, S, Evans, AC (2001). Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients. Psychiatry Research 107, 7585.
Owens, SF, Picchioni, MM, Rijsdijk, FV, Stahl, D, Vassos, E, Rodger, AK, Collier, DA, Murray, RM, Toulopoulou, T (2011). Genetic overlap between episodic memory deficits and schizophrenia: results from the Maudsley Twin Study. Psychological Medicine 41, 521532.
Ranganath, C, Minzenberg, MJ, Ragland, JD (2008). The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biological Psychiatry 64, 1825.
Schacter, DL, Wagner, AD (1999). Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus 9, 724.
Seidman, LJ, Faraone, SV, Goldstein, JM, Kremen, WS, Horton, NJ, Makris, N, Toomey, R, Kennedy, D, Caviness, VS, Tsuang, MT (2002). Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Archives of General Psychiatry 59, 839849.
Snitz, BE, MacDonald, AW 3rd, Carter, CS (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin 32, 179194.
Squire, LR, Stark, CE, Clark, RE (2004). The medial temporal lobe. Annual Review of Neuroscience 27, 279306.
Tamminga, CA, Thomas, BP, Chin, R, Mihalakos, P, Youens, K, Wagner, AD, Preston, AR (2012). Hippocampal novelty activations in schizophrenia: disease and medication effects. Schizophrenia Research 138, 157163.
Thermenos, HW, Seidman, LJ, Poldrack, RA, Peace, NK, Koch, JK, Faraone, SV, Tsuang, MT (2007). Elaborative verbal encoding and altered anterior parahippocampal activation in adolescents and young adults at genetic risk for schizophrenia using FMRI. Biological Psychiatry 61, 564574.
Thimm, M, Krug, A, Markov, V, Krach, S, Jansen, A, Zerres, K, Eggermann, T, Stocker, T, Shah, NJ, Nothen, MM, Rietschel, M, Kircher, T (2010). The impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval. Human Brain Mapping 31, 203209.
Toulopoulou, T, Goldberg, TE, Mesa, IR, Picchioni, M, Rijsdijk, F, Stahl, D, Cherny, SS, Sham, P, Faraone, SV, Tsuang, M, Weinberger, DR, Seidman, LJ, Murray, RM (2010). Impaired intellect and memory: a missing link between genetic risk and schizophrenia? Archives of General Psychiatry 67, 905913.
Toulopoulou, T, Morris, RG, Rabe-Hesketh, S, Murray, RM (2003 a). Selectivity of verbal memory deficit in schizophrenic patients and their relatives. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 116B, 17.
Toulopoulou, T, Picchioni, M, Rijsdijk, F, Hua-Hall, M, Ettinger, U, Sham, P, Murray, R (2007). Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Archives of General Psychiatry 64, 13481355.
Toulopoulou, T, Rabe-Hesketh, S, King, H, Murray, RM, Morris, RG (2003 b). Episodic memory in schizophrenic patients and their relatives. Schizophrenia Research 63, 261271.
Tulving, E (1983). Elements of Episodic Memory. Oxford University Press: New York.
Wagner, AD, Poldrack, RA, Eldridge, LL, Desmond, JE, Glover, GH, Gabrieli, JD (1998). Material-specific lateralization of prefrontal activation during episodic encoding and retrieval. Neuroreport 9, 37113717.
Wechsler, D (1954). A standardized memory scale for clinical use. Journal of Psychology 19, 8795.
Weinberger, DR (1999). Cell biology of the hippocampal formation in schizophrenia. Biological Psychiatry 45, 395402.
Whyte, MC, Whalley, HC, Simonotto, E, Flett, S, Shillcock, R, Marshall, I, Goddard, NH, Johnstone, EC, Lawrie, SM (2006). Event-related fMRI of word classification and successful word recognition in subjects at genetically enhanced risk of schizophrenia. Psychological Medicine 36, 14271439.
Wright, IC, Rabe-Hesketh, S, Woodruff, PW, David, AS, Murray, RM, Bullmore, ET (2000). Meta-analysis of regional brain volumes in schizophrenia. American Journal of Psychiatry 157, 1625.

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