Failure of deactivation in the default mode network: a trait marker for schizophrenia? R. Landin-Romero 1,2 , P. J. McKenna 1,2,3 *, P. Salgado-Pineda 1,2 , S. Sarró 1,2 , C. Aguirre 1,3 , C. Sarri 1,3 , A. Compte 1,3 , C. Bosque 1,3 , J. Blanch 4 , R. Salvador 1,2 and E. Pomarol-Clotet 1,2 1 FIDMAG Germanes Hospitalàries, Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain 3 Benito Menni Complex Assistencial en Salut Mental, Barcelona, Spain 4 Hospital Sant Joan de Déu Infantil, Barcelona, Spain Background. Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particu- larly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen. Method. A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups. Results. In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives. Conclusions. Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia. Received 29 April 2013; Revised 4 September 2014; Accepted 9 September 2014 Key words: Default mode network, endophenotype, fMRI, schizophrenia, working memory. Introduction While the existence of a genetic factor in the aetiology of schizophrenia is uncontroversial (e.g. Gottesman, 1991), studies to date have yielded only a few candi- date genes, whose effects are small and some of which are also implicated in other forms of major psy- chiatric disorder (Craddock & Owen, 2005; Collins & Sullivan, 2013). This, coupled with evidence that schizophrenia shows a complex pattern of inheritance – i.e. involving multiple genes and almost certainly environ- mental factors as well (McGue & Gottesman, 1989) – has led to a search for so-called endophenotypes, clinical or biological findings that are more closely related to risk genes than the disorder itself (Leboyer et al. 1998; Gottesman & Gould, 2003). A key aspect of the endophenotype concept is that the abnormality is pres- ent not only in patients with schizophrenia but is also seen to a lesser degree in non-affected family members at a higher rate than in the general population. The first recognizably endophenotypic construct in schizophrenia was schizotypy, a quantitative person- ality trait with presumptive neurobiological correlates (Meehl, 1962). A number of other endophenotypes have since been proposed, ranging from eye-tracking dysfunction to sensory gating deficits, cognitive im- pairment, neurological soft signs and brain structural abnormality (for a review, see Allen et al. 2009). A further candidate is brain functional abnormality; here interest has focused on the reduced dorsolateral prefrontal cortex (DLPFC) activation that is well docu- mented in schizophrenia (Hill et al. 2004), and more re- cently the ‘hyperfrontality’ or increased activation that has also been found during cognitive task performance (Weinberger et al. 2001; Minzenberg et al. 2009). MacDonald et al. (2009) reviewed 20 task-related func- tional imaging studies carried out on first-degree * Address for correspondence: P. J. McKenna, FIDMAG, Germanes Hospitalàries, Benito Menni CASM, C/. Dr Antoni Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain. (Email: mckennapeter1@gmail.com) Psychological Medicine, Page 1 of 11. © Cambridge University Press 2014 doi:10.1017/S0033291714002426 ORIGINAL ARTICLE