COMT genotype and its role on hippocampal–prefrontal regions in declarative memory Sören Krach b, ⁎ ,1 , Andreas Jansen b,1 , Axel Krug a , Valentin Markov c , Markus Thimm c , Abigail J Sheldrick c , Thomas Eggermann d , Klaus Zerres d , Tony Stöcker e , N Jon Shah e , Tilo Kircher a a Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany b Department of Psychiatry and Psychotherapy, Section of Brain Imaging, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany c Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany d Institute of Human Genetics, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany e Institute of Neuroscience and Biophysics 3-Medicine, Research Center Jülich, Germany abstract article info Article history: Received 4 August 2009 Revised 3 December 2009 Accepted 22 December 2009 Available online 11 January 2010 Keywords: COMT fMRI Schizophrenia Memory encoding Memory retrieval Hippocampus Prefrontal cortex Introduction: Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal–prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val 158 met status on the neural correlates of declarative memory was investigated in healthy subjects. Methods: From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val 158 met status was determined for the whole sample and correlated with cortical activation within the group of n = 84 individuals. Results: There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval. Discussion: Although declarative memory performance was unaffected, the neural correlates within hippocampal–prefrontal regions demonstrate a link between COMT val 158 met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia. © 2010 Elsevier Inc. All rights reserved. Introduction Memory impairments are one of the key deficits in schizophrenia (Dickinson et al., 2007). Meta-analyses show that about two thirds of the patients perform below the median of aggregated patient/control samples (Heinrichs and Zakzanis 1998). These impairments are already present in the prodromal state of schizophrenia (e.g. Simon et al., 2007) as well as in relatives of patients (Barrantes-Vidal et al., 2007; Dickinson et al., 2007; Ma et al., 2007; Myles-Worsley et al., 2007), c.f. review in (Brewer et al., 2006). Especially, in tasks involving the long-term maintenance and retrieval of verbal or figural material patients with schizophrenia have significant impairments (Tracy et al., 2001). Lesion and more recently functional neuroimaging studies have consistently demonstrated the hippocampal formation (i.e. parahip- pocampal gyrus, subiculum, hippocampus proper) as well as the prefrontal cortex (PFC) as the main cortical sites that orchestrate memory processes (Brewer et al., 1998; Cabeza and Nyberg 2000; Callicott et al., 1999; Fernandez and Tendolkar 2001; Kircher et al., 2008; Nystrom et al., 2000; Wagner et al., 1998). The hippocampus proper is the central area implicated in the formation and retrieval of item–item associations (Henke et al., 1997) and contextual bindings (Boyer et al., 2007), while the PFC supports effortful associative processing strategies by suppressing irrelevant information (Cabeza and Nyberg 2000; Fernandez and Tendolkar 2001). Hence, hippocampal as well as prefrontal regions implement processes that support declarative (episodic/semantic encoding and retrieval) memory performance (Cabeza and Nyberg 2000; Callicott et al., 1999; Nystrom et al., 2000). Meta-analytical findings suggest that patients with schizophrenia exhibit profound hypoactivations of the bilateral prefrontal cortices and the hippo- campus proper during memory encoding and retrieval tasks (Achim and Lepage 2005; Keshavan et al., 2002; Kircher et al., 2005; Leube et al., 2001; Leube et al., 2003a;b; Perlstein et al., 2003) and thus NeuroImage 53 (2010) 978–984 ⁎ Corresponding author. Fax: +49 6421 5868939. E-mail address: krachs@med.uni-marburg.de (S. Krach). 1 Both authors contributed equally. 1053-8119/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.12.090 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg