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Executive functioning-related brain abnormalities associated with the genetic liability for schizophrenia: an activation likelihood estimation meta-analysis

Published online by Cambridge University Press:  14 October 2010

V. M. Goghari
V. M. Goghari*
Affiliation:
Clinical Neuroscience of Schizophrenia (CNS) Laboratory, Department of Psychology and Psychiatry, University of Calgary, Calgary, AB, Canada
*
*Address for correspondence: V. M. Goghari, Ph.D., Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, AB, Canada T2N 1N4. (Email: vina.m.goghari@ucalgary.ca)
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Abstract

Background

Relatives of schizophrenia patients demonstrate abnormalities in prefrontal cortical activation during executive processing as measured by functional neuroimaging, albeit not consistently. A meta-analysis was conducted to determine whether reliable patterns of brain hypo- and hyperactivity, especially in the middle frontal region, were present in the relatives of patients.

Method

Seventeen studies, containing 18 samples of relatives and controls, were included in this meta-analysis. Studies were included if relatives of schizophrenia patients were compared to controls, an executive processing task was used, and standard space coordinates were reported for the functional activations. Activation likelihood estimation (ALE) was implemented to find convergence across functional neuroimaging experiment coordinates. A separate analysis was conducted to assess the potential impact of a priori hypothesis testing used in region-of-interest (ROI) approaches on the meta-analysis results.

Results

Relatives demonstrated hypo- and hyperactivity in statistically overlapping right middle frontal regions [Brodmann area (BA) 9/10]. Use of an ROI analysis that a priori focused on prefrontal regions resulted in more findings of reduced activity in the middle frontal region.

Conclusions

The cortical regions identified by this meta-analysis could potentially serve as intermediate biological markers in the search for candidate genes for schizophrenia. As neurocognitive deficits are related to functional impairments in patients, a better understanding of neural and genetic vulnerabilities would be beneficial in our efforts to remediate these important deficits.

Keywords

Cognitionendophenotypefamily studyfunctional magnetic resonance imaging (fMRI)prefrontal cortex
Type
Original Articles
Information
Psychological Medicine , Volume 41 , Issue 6 , June 2011 , pp. 1239 - 1252
Copyright
Copyright © Cambridge University Press 2010

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References

Achim, AM, Lepage, M (2005). Episodic memory-related activation in schizophrenia: meta-analysis. British Journal of Psychiatry 187, 500–509.Google Scholar
Becker, TM, Kerns, JG, MacDonald, AW 3rd, Carter, CS (2008). Prefrontal dysfunction in first-degree relatives of schizophrenia patients during a Stroop task. Neuropsychopharmacology 33, 2619–2625.CrossRefGoogle ScholarPubMed
Boos, HB, Aleman, A, Cahn, W, Pol, HH, Kahn, RS (2007). Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Archives of General Psychiatry 64, 297–304.Google Scholar
Brahmbhatt, SB, Haut, K, Csernansky, JG, Barch, DM (2006). Neural correlates of verbal and nonverbal working memory deficits in individuals with schizophrenia and their high-risk siblings. Schizophrenia Research 87, 191–204.CrossRefGoogle ScholarPubMed
Braver, TS, Gray, JR, Burgess, GC (2007). Explaining the many varieties of working memory variation: dual mechanisms of cognitive control. In Variation in Working Memory (ed. Conway, A. R. A., Jarrold, C., Kane, M. J., Miyake, A. and Towse, J. N.), pp. 76–106. Oxford University Press: New York, NY.Google Scholar
Callicott, JH, Egan, MF, Mattay, VS, Bertolino, A, Bone, AD, Verchinksi, B, Weinberger, DR (2003). Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. American Journal of Psychiatry 160, 709–719.CrossRefGoogle ScholarPubMed
Camchong, J, Dyckman, KA, Austin, BP, Clementz, BA, McDowell, JE (2008). Common neural circuitry supporting volitional saccades and its disruption in schizophrenia patients and relatives. Biological Psychiatry 64, 1042–1050.Google Scholar
Carter, CS, Heckers, S, Nichols, T, Pine, DS, Strother, S (2008). Optimizing the design and analysis of clinical functional magnetic resonance imaging research studies. Biological Psychiatry 64, 842–849.Google Scholar
Costafreda, SG, Fu, CHY, Picchioni, M, Kane, F, McDonald, C, Prata, DP, Kalidindi, S, Walshe, M, Curtis, V, Bramon, E, Kravariti, E, Marshall, N, Toulopoulou, T, Barker, GJ, David, AS, Brammer, MJ, Murray, RM, McGuire, PK (2009). Increased inferior frontal activation during word generation: a marker of genetic risk for schizophrenia but not bipolar disorder? Human Brain Mapping 30, 3287–3298.Google Scholar
Delawalla, Z, Csernansky, JG, Barch, DM (2008). Prefrontal cortex function in nonpsychotic siblings of individuals with schizophrenia. Biological Psychiatry 63, 490–497.Google Scholar
Eickhoff, SB, Laird, AR, Grefkes, C, Wang, LE, Zilles, K, Fox, PT (2009). Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Human Brain Mapping 30, 2907–2926.Google Scholar
Faraone, SV, Seidman, LJ, Kremen, WS, Toomey, R, Lyons, MJ, Tsuang, MT (1996). Neuropsychological functioning among the elderly nonpsychotic relatives of schizophrenic patients. Schizophrenia Research 21, 27–31.CrossRefGoogle ScholarPubMed
Filbey, FM, Russell, T, Morris, RG, Murray, RM, McDonald, C (2008). Functional magnetic resonance imaging (fMRI) of attention processes in presumed obligate carriers of schizophrenia: preliminary findings. Annals of General Psychiatry 7, 18.CrossRefGoogle ScholarPubMed
Glahn, DC, Laird, AR, Ellison-Wright, I, Thelen, SM, Robinson, JL, Lancaster, JL, Bullmore, E, Fox, PT (2008). Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biological Psychiatry 64, 774–781.Google Scholar
Glahn, DC, Ragland, JD, Abramoff, A, Barrett, J, Laird, AR, Bearden, CE, Velligan, DI (2005). Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping 25, 60–69.CrossRefGoogle ScholarPubMed
Gottesman, II (1991). Schizophrenia Genesis: The Origins of Madness. Freeman: New York.Google Scholar
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645.Google Scholar
Green, MF (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry 153, 321–330.Google ScholarPubMed
Green, MF, Kern, RS, Braff, DL, Mintz, J (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the ‘right stuff’? Schizophrenia Bulletin 26, 119–136.CrossRefGoogle ScholarPubMed
Harrison, PJ, Weinberger, DR (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry 10, 40–68.Google Scholar
Heinrichs, RW (2005). The primacy of cognition in schizophrenia. American Psychologist 60, 229–242.CrossRefGoogle ScholarPubMed
Heinrichs, RW, Zakzanis, KK (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426–445.Google Scholar
Karlsgodt, KH, Glahn, DC, van Erp, TG, Therman, S, Huttunen, M, Manninen, M, Kaprio, J, Cohen, MS, Lonnqvist, J, Cannon, TD (2007). The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects. Schizophrenia Research 89, 191–197.Google Scholar
Keshavan, MS, Diwadkar, VA, Spencer, SM, Harenski, KA, Luna, B, Sweeney, JA (2002). A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26, 1143–1149.CrossRefGoogle ScholarPubMed
Laird, AR, Fox, PM, Price, CJ, Glahn, DC, Uecker, AM, Lancaster, JL, Turkeltaub, PE, Kochunov, P, Fox, PT (2005). ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Human Brain Mapping 25, 155–164.CrossRefGoogle ScholarPubMed
Lancaster, JL, Tordesillas-Gutierrez, D, Martinez, M, Salinas, F, Evans, A, Zilles, K, Mazziotta, JC, Fox, PT (2007). Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template. Human Brain Mapping 28, 1194–1205.CrossRefGoogle ScholarPubMed
Lancaster, JL, Woldorff, MG, Parsons, LM, Liotti, M, Freitas, CS, Rainey, L, Kochunov, PV, Nickerson, D, Mikiten, SA, Fox, PT (2000). Automated Talairach atlas labels for functional brain mapping. Human Brain Mapping 10, 120–131.Google Scholar
MacDonald, AW 3rd, Becker, TM, Carter, CS (2006). Functional magnetic resonance imaging study of cognitive control in the healthy relatives of schizophrenia patients. Biological Psychiatry 60, 1241–1249.CrossRefGoogle ScholarPubMed
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, 1142–1162.CrossRefGoogle ScholarPubMed
Manoach, DS (2003). Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophrenia Research 60, 285–298.CrossRefGoogle ScholarPubMed
Meda, SA, Bhattarai, M, Morris, NA, Astur, RS, Calhoun, VD, Mathalon, DH, Kiehl, KA, Pearlson, GD (2008). An fMRI study of working memory in first-degree unaffected relatives of schizophrenia patients. Schizophrenia Research 104, 85–95.CrossRefGoogle ScholarPubMed
Minzenberg, MJ, Laird, AR, Thelen, S, Carter, CS, Glahn, DC (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Archives of General Psychiatry 66, 811–822.Google Scholar
Poldrack, RA, Fletcher, PC, Henson, RN, Worsley, KJ, Brett, M, Nichols, TE (2008). Guidelines for reporting an fMRI study. NeuroImage 40, 409–414.Google Scholar
Raemaekers, M, Ramsey, NF, Vink, M, van den Heuvel, MP, Kahn, RS (2006). Brain activation during antisaccades in unaffected relatives of schizophrenic patients. Biological Psychiatry 59, 530–535.Google Scholar
Ragland, JD, Laird, AR, Ranganath, C, Blumenfeld, RS, Gonzales, SM, Glahn, DC (2009). Prefrontal activation deficits during episodic memory in schizophrenia. American Journal of Psychiatry 166, 863–874.Google Scholar
Seidman, LJ, Thermenos, HW, Koch, JK, Ward, M, Breiter, H, Goldstein, JM, Goodman, JM, Faraone, SV, Tsuang, MT (2007). Auditory verbal working memory load and thalamic activation in nonpsychotic relatives of persons with schizophrenia: an fMRI replication. Neuropsychology 21, 599–610.CrossRefGoogle ScholarPubMed
Seidman, LJ, Thermenos, HW, Poldrack, RA, Peace, NK, Koch, JK, Faraone, SV, Tsuang, MT (2006). Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory. Schizophrenia Research 85, 58–72.CrossRefGoogle Scholar
Sepede, G, Ferretti, A, Perrucci, MG, Gambi, F, Di Donato, F, Nuccetelli, F, Del Gratta, C, Tartaro, A, Salerno, RM, Ferro, FM, Romani, GL (2010). Altered brain response without behavioral attention deficits in healthy siblings of schizophrenic patients: an event-related fMRI study. NeuroImage 49, 1080–1090.CrossRefGoogle ScholarPubMed
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, 179–194.Google Scholar
Spaniel, F, Tintera, J, Hajek, T, Horacek, J, Dezortova, M, Hajek, M, Dockery, C, Kozeny, J, Hoschl, C (2007). Language lateralization in monozygotic twins discordant and concordant for schizophrenia. A functional MRI pilot study. European Psychiatry 22, 319–322.Google Scholar
Tan, HY, Callicott, JH, Weinberger, DR (2009). Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms. Cognitive Neuropsychiatry 14, 277–298.Google Scholar
Thermenos, HW, Seidman, LJ, Breiter, H, Goldstein, JM, Goodman, JM, Poldrack, R, Faraone, SV, Tsuang, MT (2004). Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study. Biological Psychiatry 55, 490–500.CrossRefGoogle ScholarPubMed
Vink, M, Ramsey, NF, Raemaekers, M, Kahn, RS (2006). Striatal dysfunction in schizophrenia and unaffected relatives. Biological Psychiatry 60, 32–39.CrossRefGoogle ScholarPubMed
Williams, HJ, Owen, MJ, O'Donovan, MC (2009). New findings from genetic association studies of schizophrenia. Journal of Human Genetics 54, 9–14.Google Scholar
Woodward, ND, Waldie, B, Rogers, B, Tibbo, P, Seres, P, Purdon, SE (2009). Abnormal prefrontal cortical activity and connectivity during response selection in first episode psychosis, chronic schizophrenia, and unaffected siblings of individuals with schizophrenia. Schizophrenia Research 109, 182–190.Google Scholar