Psychological Medicine Autobiographical memory and default cambridge.org/psm mode network function in schizophrenia: an fMRI study‡ Marta Martin-Subero1,2,3,*, Paola Fuentes-Claramonte1,2,*, Pilar Salgado-Pineda1,2, Original Article Josep Salavert1,3,4, Antoni Arevalo1,5, Clara Bosque1,6, Carmen Sarri1,6, *These authors contributed equally to this study. Amalia Guerrero-Pedraza1,6, Aniol Santo-Angles1, Antoni Capdevila7,8, ‡The online version of this article has been Salvador Sarró1,2, Raymond Salvador1,2, Peter J. McKenna1,2 updated since original publication. A notice detailing the changes has also been published and Edith Pomarol-Clotet1,2 at https://doi.org/10.1017/S0033291720001361 1 FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; 2CIBERSAM (Centro de Investigación Cite this article: Martin-Subero M et al (2021). Biomédica en Red de Salud Mental), Madrid, Spain; 3Department of Psychiatry and Forensic Medicine, Universitat Autobiographical memory and default mode Autònoma de Barcelona, Barcelona, Spain; 4Psychiatry Department, Hospital Sant Rafael, Barcelona, Spain; 5 network function in schizophrenia: an fMRI Psychiatry Department, Hospital Sagrat Cor Martorell Barcelona, Barcelona, Spain; 6Benito Menni Centre study. Psychological Medicine 51, 121–128. Assistencial en Salut Mental, Sant Boi de Llobregat, Barcelona, Spain; 7Radiology Unit, Hospital de la Santa Creu i https://doi.org/10.1017/S0033291719003052 Sant Pau (HSCSP), Barcelona, Spain and 8CIBER-BBN (Centro de Investigación Biomédica en Red en Bioingeniería, Received: 12 December 2018 Biomateriales y Nanomedicina), Zaragoza, Spain Revised: 23 September 2019 Accepted: 3 October 2019 Abstract First published online: 4 November 2019 Background. The brain functional correlates of autobiographical recall are well established, Key words: but have been little studied in schizophrenia. Additionally, autobiographical memory is one Autobiographical memory; default mode of a small number of cognitive tasks that activates rather than de-activates the default network; fMRI; schizophrenia mode network, which has been found to be dysfunctional in this disorder. Author for correspondence: Methods. Twenty-seven schizophrenic patients and 30 healthy controls underwent functional mag- Peter J. McKenna, netic resonance imaging while viewing cue words that evoked autobiographical memories. Control E-mail: mckennapeter1@gmail.com conditions included both non-memory-evoking cues and a low level baseline (cross fixation). Results. Compared to both non-memory evoking cues and low level baseline, autobiographical recall was associated with activation in default mode network regions in the controls including the medial frontal cortex, the posterior cingulate cortex and the hippocampus, as well as other areas. Clusters of de-activation were seen outside the default mode network. There were no acti- vation differences between the schizophrenic patients and the controls, but the patients showed clusters of failure of de-activation in non-default mode network regions. Conclusions. According to this study, patients with schizophrenia show intact activation of the default mode network and other regions associated with recall of autobiographical mem- ories. The finding of failure of de-activation outside the network suggests that schizophrenia may be associated with a general difficulty in de-activation rather than dysfunction of the default mode network per se. Autobiographical recall refers to the conscious re-imagining of events from one’s past, with the memories typically being accompanied by some of their original sensory and emotional qual- ities (Rubin, 1996; Svoboda et al., 2006). Autobiographical memory forms part of the broader construct of episodic memory, but differently from standard episodic memory tasks, which employ experimenter-generated stimuli such as lists of words, it is tested by asking subjects to recall memorable events in their own lives. These may be elicited in response to cue words like ‘river’ or ‘puppy’ (the Crovitz task; Crovitz and Schiffman, 1974), or by means of prompts about events such as starting a new job or attending a wedding (the Autobiographical Memory Test, AMI; Kopelman et al., 1989). Autobiographical memory has been linked conceptually to the ability to imagine future events, and together they form the concept of ‘mental time travel’ (Schacter et al., 2007). Autobiographical memory has also been argued to play a key role in the construction of one’s sense of self (Conway and © The Author(s) 2019. This is an Open Access Pleydell-Pearce, 2000). article, distributed under the terms of the As expected, given the evidence for episodic memory impairment in the disorder Creative Commons Attribution licence (http:// creativecommons.org/licenses/by/4.0/), which (e.g. Palmer et al., 2009), autobiographical memory has been found to be impaired in schizo- permits unrestricted re-use, distribution, and phrenia. A meta-analysis of 20 studies (Berna et al., 2016) found significantly poorer perform- reproduction in any medium, provided the ance compared to healthy controls in all aspects of autobiographical recall examined; effect original work is properly cited. sizes were large for richness of detail and specificity of memories, and moderate for conscious recollection, i.e. the degree of personal awareness of participating in the re-experienced events. To date, there has been only one study of the brain functional correlates of autobiographical recall in schizophrenia: Cuervo-Lombard et al. (2012) compared 13 schizophrenic patients and 14 healthy controls using a task where they saw cue words and pressed a button when they 122 Marta Martin-Subero et al. recalled a personal event associated with them. The control task Given the evidence for failure of default mode de-activation consisted of a button press in response to instructions to use (and perhaps increased de-activation in some circumstances) in either the middle or index finger to do this. Whole-brain func- schizophrenia, how the network behaves during a task like auto- tional magnetic resonance imaging (fMRI) with correction for biographical memory, which normally activates it, is clearly of multiple comparisons revealed no major clusters of significant some interest. In the current study, we examined both activations difference between the groups in the cortex, but there were and de-activations associated with autobiographical recall in small clusters of reduced activation in the patients in the lateral schizophrenia, using a larger sample of patients and controls ventral tegmental area, the right cerebellum and both caudate than in Cuervo-Lombard et al.’s (2012) study and employing nuclei. Uncorrected comparisons within a mask comprising the whole-brain analysis with correction for multiple comparisons. areas activated by the patients and/or the controls, however, revealed additional areas of reduced activation in the patients in the medial frontal cortex, the precuneus, the left lateral prefrontal Methods cortex, the left medial temporal lobe and the occipital cortex. Subjects Autobiographical recall is also of interest from the functional imaging point of view because it has been found to activate the The patient sample consisted of 27 right-handed patients meeting so-called default mode network (Buckner et al., 2008; Raichle, DSM-IV criteria for schizophrenia, recruited from three psychi- 2015). This network consists of a set of brain regions that are nor- atric hospitals in Barcelona (Benito Menni CASM, Hospital mally active at rest but which de-activate during performance of a Sagrat Cor de Martorell and Sant Rafael Hospital). The diagnosis wide range of attention-demanding tasks. It includes prominently was established using the Structured Clinical Interview for DSM two midline areas, the medial prefrontal cortex and the posterior Disorders (SCID) (First et al., 2002). Patients were excluded if cingulate cortex/precuneus, as well as parts of the parietal and tem- they (a) were younger than 18 or older than 65, (b) had a history poral lobe cortex and the hippocampus (Gusnard and Raichle, 2001; of brain trauma or neurological disease or (c) had shown alcohol/ Raichle et al., 2001; Buckner et al., 2008). The small number of tasks substance abuse/dependence within 12 months prior to participa- that have been found to activate rather than de-activate the default tion. With respect to the last criterion, all participants were ques- mode network regions include imagining the future (Schacter et al., tioned about alcohol and drug use during the previous year, and 2007), making judgements about oneself and others (van der Meer we also excluded those who reported habitual use of cannabis. et al., 2010; Murray et al., 2012), making moral judgements Social use of alcohol was permitted, as was non-habitual use of (Boccia et al., 2017), engaging in theory of mind-type reasoning cannabis. All the patients were taking antipsychotic treatment (Schurz et al., 2014) and autobiographical memory. With respect (23 on atypical neuroleptics, one on typical neuroleptics and to this last paradigm, Svoboda et al. (2006) meta-analysed 24 three on both). positron-emission tomography (PET) and fMRI studies using The control sample consisted of 30 right-handed healthy indi- autobiographical memory tasks and found pooled evidence of viduals recruited from non-clinical staff working in the hospitals, activations in the medial frontal cortex and the retrosplenial/ their relatives and acquaintances, plus independent sources in the posterior cingulate cortex, i.e. the two midline cortical ‘nodes’ of community. They met the same exclusion criteria as the patients the default mode network, as well as other regions including the and they were also interviewed using the SCID to exclude current dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal and past psychiatric disorders. They were questioned and also cortex, other lateral prefrontal regions, the medial and lateral excluded if they reported a history of treatment with psychotropic temporal cortex, the temporoparietal junction and the cerebellum. medication beyond non habitual use of night sedation. Default mode network dysfunction during performance of vari- The two groups were selected to be matched for age, sex and ous cognitive tasks has been reported in schizophrenia since 2007. estimated IQ (premorbid IQ in the patients). This latter was mea- Two initial studies (Garrity et al., 2007; Harrison et al., 2007) found sured using the Word Accentuation Test (Test de Acentuación de increased de-activation or a mixed pattern of increased activation Palabras, TAP; Del Ser et al., 1997; Gomar et al., 2011). All and failure of de-activation, respectively. Since then, however, the patients were scanned when in a relatively stable condition. almost invariable finding has been failure of de-activation, which All participants gave written informed consent. All the study is typically seen in the medial frontal cortex (Pomarol-Clotet procedures were approved by the local research ethics committee. et al., 2008; Whitfield-Gabrieli et al., 2009; Mannell et al., 2010; Salgado-Pineda et al., 2011; Schneider et al., 2011; Dreher et al., Autobiographical memory task 2012; Haatveit et al., 2016), although the posterior cingulate gyrus/precuneus has also sometimes been found to be affected The task used was based on the one developed by Oertel-Knochel (Salgado-Pineda et al., 2011; Schneider et al., 2011). There appear et al. (2012), which employed personalised cues that had previ- to be only two exceptions: using a visual working memory task ously been found to evoke autobiographical memories in the sub- with various levels of difficulty, Hahn et al. (2017) found that 21 jects. While they employed a control which involved completing a schizophrenic patients and 16 controls showed no differences in sentence with a semantically appropriate word, we changed this to de-activation across 13 regions of interest placed in the default one involving viewing of cues that had previously been found not mode network, and at the two hardest levels de-activation was to evoke autobiographical memories. significantly greater in the patients. In another study using a task Before the fMRI session, each participant was administered the requiring direction of attention to visual stimuli that either cue words from the Crovitz test (Crovitz and Schiffman, 1974) predicted or did not predict the location of a subsequent target, and the autobiographical prompt phrases from the AMI the same group (Hahn et al., 2016) again found no differences in (Kopelman et al., 1989), in order to generate between four and default mode network de-activation in 20 schizophrenic patients six autobiographical memories for each of the time periods cover- compared to 20 healthy controls (when the cue was predictive) ing childhood, adolescence, adulthood and the preceding year. or greater de-activation (when the cue was non-predictive). The stimuli chosen for the fMRI paradigm consisted of groups Psychological Medicine 123 of three words personalised for each participant. The first word in comparison between conditions. Group comparisons between the group referred to one of the above four time periods, and the patients and controls were performed within the FEAT module, other two words were chosen on the basis that they had previously with mixed-effects GLMs (Beckmann et al., 2006). evoked autobiographical memories (e.g. childhood-grandmother- Statistical tests were carried out at the cluster level with a cor- cake; adult-car-robbery). All memories were required to have rected p value of 0.05 using Gaussian random field methods. A been given the maximum score of 3 in the AMI, indicating that threshold of z = 3.1 was used to define the initial set of clusters. they were clearly specified in time and place and descriptively rich. For the control conditions, we randomly selected groups of three words from the words that did not evoke autobiographical Contrasts used in the analysis memories. In order to examine autobiographical memory associated activa- Ten blocks of non-memory-evoking stimuli were alternated tions, the main contrast employed was that between cues that with ten blocks of memory-evoking stimuli; all blocks lasted evoked and did not evoke autobiographical memories, something 20 s. Each block contained two cue sentences of the appropriate that should eliminate ‘noise’ due to aspects of performance type. Subjects were instructed to recollect the memory previously common to both tasks. evoked by the three word phrase, or in the case of the For de-activations, we focused on the contrast between non-memory-evoking phrase, to read the phrase with no further memory-evoking cues and the low level baseline. This was to requirements. A low level baseline condition was also employed, avoid a methodological problem identified by Gusnard and cross fixation. This was presented between blocks for 16 s. Raichle (2001), that examination of relative changes between two At the end of the scanning session all participants were asked active tasks will not necessarily reveal the true picture of activations what they had been thinking about during each condition. and de-activations. Specifically, because fMRI analysis is subtract- Specifically, we asked if they could recollect the memories that ive, task-associated decreases in activation will be obtained not they reported in the previous interview during the memory-evoking only when there is greater de-activation from baseline levels in condition, and whether they were wide awake and focused during the task of interest (in this case memory evoking cues) than in the session. Participants who responded negatively to either of the control task (in this case non-memory-evoking cues), but these questions were excluded. also if there is greater activation from baseline levels in the control task than in the task of interest. It follows that de-activations can Image acquisition only be confidently identified with respect to a low level baseline. Images were acquired with a 3T Philips Achieva scanner (Philips Medical Systems, Best, The Netherlands). Functional data were Results acquired using a T2*-weighted echo-planar imaging (EPI) sequence Demographic data with the following acquisition parameters: TR = 2000 ms, TE = 30 ms, flip angle = 78°, in-plane resolution = 3 × 3 mm, Age, sex and TAP-estimated IQ data for the patients and controls FOV = 240 mm, slice thickness = 3 mm, inter-slice gap = 1 mm. are shown in Table 1. As can be seen, the two groups were The autobiographical memory task consisted of 360 volumes. matched on all three variables. None of the patients and two of Slices (32 per volume) were acquired with an interleaved order the controls reported sporadic use of cannabis. parallel to the AC-PC plane. Before the functional sequences, a high-resolution anatomical 3D volume was acquired using a fMRI findings: memory-evoking v. non-memory evoking cues Turbo Field Echo sequence for anatomical reference and inspection (TR = 8.15 ms; TE = 3.73 ms; flip angle = 8°; voxel size = 0.9375 × In this contrast the healthy controls showed a large cluster of 0.9375 mm; slice thickness = 1 mm; slice number = 160; greater activation to the memory-evoking cues than the FOV = 240 mm). non-memory-evoking cues in the medial frontal cortex extending Any subjects with excessive head movement during the fMRI to the orbitofrontal cortex and temporal poles bilaterally, as well as sequence, defined as an estimated maximum absolute movement to the thalamus, the basal ganglia, the hippocampus and the para- >3.0 mm or an average absolute movement >0.3 mm, were hippocampal cortex. This cluster also extended posteriorly to excluded. include a portion of the posterior cingulate cortex/precuneus and the calcarine cortex. Other clusters of activation included the left temporo-parietal junction (comprising the posterior portion of Image preprocessing and analysis middle temporal cortex, the angular gyrus and the middle occipital Preprocessing and analysis was carried out with the FEAT module cortex), the left middle temporal cortex, and the right angular included in the FSL (FMRIB Software Library) software (Smith gyrus (see Fig. 1, top panel, and online Supplementary Table S1). et al., 2004). The first 20 s, corresponding to signal stabilisation, The healthy controls also showed three clusters of increased were discarded. Preprocessing included motion correction activation to non-memory-evoking than to memory-evoking (using the MCFLIRT algorithm) and co-registration and normal- cues. These were in the occipital cortex bilaterally, the lateral par- isation to a common stereotactic space (MNI template). Before ietal cortex bilaterally, more in the right hemisphere, the superior group analyses, normalised images were spatially filtered with a temporal cortex bilaterally and the right frontal polar cortex. Gaussian filter (FWHM = 5 mm). The schizophrenic patients (Fig. 1, middle panel) showed a Statistical analysis was performed by means of a general linear broadly similar pattern of activation, although this appeared visu- model (GLM). Two regressors of interest were defined at the ally less extensive in the medial frontal cortex and subcortical single-subject level analysis (memory-evoking blocks and regions. Unlike the controls, they showed no regions where there non-memory-evoking blocks) and the GLM was fitted to generate was relatively greater activation in response to non-memory- activation maps of each condition compared to baseline and the evoking cues. 124 Marta Martin-Subero et al. Table 1. Demographic data for the patients and controls Healthy controls (N = 30) Schizophrenia patients (N = 27) Differences Sex (M/F) 19/11 17/10 p = 0.98 Age 40.40 (11.23) 40.15 (8.75) p = 0.93 Premorbid IQ 103.70 (6.38) 100.23 (10.90) p = 0.16 No. reporting social alcohol use 14 7 No. reporting non-habitual cannabis use 2 0 Antipsychotic dose (chlorpromazine equivalents) – 495.41 (459.01) Values for age and premorbid IQ are means (SD) Fig. 1. Areas of significant differences between the autobiographical memory-evoking and non-evoking cue conditions for the healthy subjects (a) and the schizophrenic patients (b). Warm colours represent autobiographical recall > non-memory-evoking cues, cold colours represent non-memory-evoking cues > auto- biographical recall. Bottom row (c) shows areas of significant differences between the patients and controls in this contrast. Colour bars depict Z values. Images are displayed in neurological convention (right is right). Significant group differences (Fig. 1, bottom panel) were Fig. S1. This confirmed that they all represented regions of rela- observed in four relatively small clusters: the right lingual tively greater activation in the patients. gyrus [294 voxels, peak activation at BA 19, MNI (26, −54, −4), To investigate the possible influence of antipsychotic treatment z score = 4.52, p = 0.003], the right cuneus [279 voxels, peak activa- on the above findings, the within-group analysis for the tion at BA 18, MNI (6, −90, 26), z score = 3.86, p = 0.004], the left schizophrenic patients was repeated adding medication dose (in middle temporal cortex [263 voxels, peak activation at BA 21, MNI chlorpromazine equivalents) as a covariate. The findings in this (−68, −10, −2), z score = 4.48, p = 0.006] and the right angular group remained closely similar (see online Supplementary gyrus [199 voxels, peak activation at BA 40, MNI (54, −52, 38), z Material, Fig. S2A). score = 4.03, p = 0.02]. As can be seen from Fig. 1, these clusters of significant difference were all in regions where the healthy fMRI findings: memory-evoking cues v. low level baseline controls showed greater activation to non-memory-evoking cues than to memory-evoking cues. Box plots of mean activations Compared to cross fixation, the healthy controls showed a similar within these four clusters are shown in online Supplementary but more extensive pattern of activation than in the Psychological Medicine 125 Fig. 2. Activation map for the autobiographical memory-evoking cues v. fixation condition in the healthy subjects (a) and the schizophrenic patients (b). Warm colours represent autobiographical cues > baseline. Cold colours represent baseline > autobiographical cues. The third panel (c) shows areas of significant differ- ences between the patients and the controls in this contrast. Colour bars depict Z values. Images are displayed in neurological convention (right is right). autobiographical memory-evoking v. non-evoking cue contrast. A non-evoking cues, repeating the within-group analysis for the large cluster encompassed the posterior cingulate cortex and pre- schizophrenic patients adding medication dose (in chlorpromazine cuneus, the left angular gyrus, the middle temporal cortex bilat- equivalents) as a covariate made little difference to the findings erally, parts of the lateral prefrontal cortex and anterior insula (see Supplementary Material, Fig. S2B). bilaterally and the medial prefrontal cortex, and also extended There were no regions where the patients showed less activa- to the occipital cortex, the hippocampus and parahippocampus, tion compared to cross fixation than the controls (Fig. 2, bottom the thalamus, the basal ganglia and the cerebellum. A second panel). However, the patients showed greater activation than the cluster covered the posterior portion of the right middle controls in seven clusters: the largest was in the right parietal cor- temporal cortex and right angular gyrus. The third cluster of tex [1336 voxels, peak activation at BA 40, MNI (38, −44, 50), z activation was located in the precuneus. The findings are score = 4.86, p < 0.001]; a roughly symmetrical but smaller cluster shown in Fig. 2, top panel; further details are given in online was in the left parietal cortex [563 voxels, peak activation at BA Supplementary Table S2. 40, MNI (−42, −46, 52), z score = 4.39, p < 0.001]; other clusters As can also be seen in Fig. 2, the healthy controls also showed were in the postcentral gyrus [324 voxels, peak activation at BA clusters of de-activation compared to cross fixation. There were 48, MNI (−64, −18, 22), z score = 4.08, p < 0.001]; the left bilateral clusters in the superior temporal gyrus extending to middle temporal cortex [255 voxels, peak activation at BA 22, the postcentral gyrus; the cluster on the right also extended to MNI (−62, −12, −2), z score = 5.01, p = 0.00329]; the left inferior the superior parietal cortex and parts of the posterior cingulate temporal cortex [191 voxels, peak activation at BA 37, MNI cortex and precuneus. Two more bilateral clusters were seen in (−48, −56, −8), z score = 4.58, p = 0.0145]; the left superior the inferior temporal cortex extending to the lateral occipital cor- occipital cortex [163 voxels, peak activation at BA 19, MNI tex. A fifth cluster was in the left superior parietal cortex. (−20, −74, 40), z score = 4.22, p = 0.029]; and the insula [148 vox- The patients showed a broadly similar pattern of activation to the els, peak activation at BA 48, MNI (−36, −20, 12), z score = 4.56, healthy controls, with large clusters in the medial prefrontal cortex p = 0.0426]. and the posterior cingulate cortex/precuneus, hippocampus and Box plots of the mean activations within these seven clusters parahippocampus, as well as in the lateral prefrontal cortex confirmed that in six cases they represented failure of bilaterally, the left temporal and parietal cortex and parts of de-activation in the schizophrenic patients (see Supplementary the occipital cortex bilaterally. However, they showed no clusters of Fig. S3). The seventh cluster (in the superior occipital cortex) de-activation (see Fig. 2, middle panel, and online Supplementary was in a region where the controls showed no significant Table S2). As in the contrast between memory-evoking and activation or de-activation. 126 Marta Martin-Subero et al. Discussion network as identified by de-activations in studies using attention- demanding tasks (Buckner et al., 2008) or based on resting state This study examined the brain functional correlates of autobio- connectivity (Yeo et al., 2011). graphical recall in schizophrenia, comparing it to two control The obvious interpretation of this finding is that schizophrenic tasks, viewing of non-memory evoking cues and cross fixation. patients show failure of de-activation outside the default mode Under both conditions the healthy controls showed activation network during performance of a task that normally activates it. within the territory of the default mode network, particularly in Clearly, however, such an interpretation depends on to what its two midline cortical regions. The patients did not differ signifi- extent autobiographical recall can be considered to be normally cantly from the healthy controls in the degree of activation in associated with a pattern of non-default mode network these regions. However, they did show evidence of changes, de-activation. Unfortunately, this question is difficult to answer, which took the form mainly of failure of de-activation, in regions as most studies of autobiographical recall in healthy subjects outside the default mode network. have not reported de-activations. Four early studies of autobio- The healthy controls in our study showed a pattern of autobio- graphical recall using PET noted both task related activations graphical memory associated activations that was reasonably (i.e. recall > rest) and de-activations (i.e. rest > recall) (Andreasen consistent with that found by Svoboda et al. (2006) in their et al., 1995; Fink et al., 1996; Gemar et al., 1996; Andreasen meta-analysis of 24 studies. The most important difference was et al., 1999), but the sample sizes were mostly small (7–19 sub- that, whereas Svoboda et al. (2006) found evidence of lateral jects) in these studies and the areas of de-activation varied widely. frontal activation during task performance, in our study this Only two fMRI studies appear to have reported de-activations. was only seen under the memory cue evoking condition v. low Ino et al. (2011) examined 21 healthy subjects and found greater level baseline (cross fixation), and not in the memory cue evoking activation under a ‘no thinking’ condition than during autobio- v. non-evoking contrast. One possible explanation for this differ- graphical recall in the temporal poles, orbitofrontal cortex, poster- ence might be that the participants actively engaged in search (i.e. ior insula, and portions of the bilateral middle/superior temporal, executive) strategies during both the active conditions, before inferior parietal, and occipital cortex. De-activation was also either locating or failing to locate a relevant autobiographical observed in the mid-cingulate cortex and precuneus, extending memory. Some support for this explanation comes from a study into the superior parietal cortex. Bado et al. (2014) examined of healthy subjects by Cabeza et al. (2004) which, as in our 18 healthy subjects and found greater activation during a ‘relax study, contrasted cues designed to both elicit and not elicit auto- and stay awake’ condition than during recall of both emotional biographical memories (in this case, photographs of a university and neutral autobiographical memories in the subgenual anterior campus taken by the subject him-or herself or by others). cingulate cortex, the ventral striatum and the hypothalamus/septal Both conditions were found to activate the dorsolateral and area, and additionally in the inferior parietal lobe bilaterally dur- ventrolateral prefrontal cortex compared to cross fixation, with ing recall of emotional memories. Collectively, these findings sup- no differences being found between the two active conditions. port the idea that autobiographical recall is associated with Our findings in schizophrenic patients differ markedly from de-activations, and there are hints of an overlap with the findings those of the only other study to date, that of Cuervo-Lombard from our own group of healthy controls. et al. (2012). These authors found reduced activation in the The only other relevant data come from a study by DuPre et al. patients in the medial frontal cortex and the precuneus, and (2016) in which 31 healthy adults viewed emotional pictures and also in the left lateral prefrontal cortex, the left medial temporal engaged in autobiographical recall, prospection or theory of mind lobe and other areas, whereas we found no evidence of reduced reasoning based on their content. Data from this study are pub- activation in any region. However, there is an obvious potential licly available at NeuroVault (https://neurovault.org/collections/ explanation for this discrepancy: as noted in the introduction, 1866/). Contrasting self-generated thought (i.e. combining all Cuervo-Lombard et al.’s (2012) findings of reduced cortical three task conditions) to a baseline consisting of viewing a activation in the schizophrenic patients were only obtained scrambled image followed by a button press, clusters of when a masked analysis using an uncorrected threshold was de-activation were seen in the parietal and temporal regions not employed; whole brain corrected analysis revealed differences dissimilar to those we observed in our study, as well as in the between the patients and the controls only in small clusters occipital cortex. located in non-cortical regions. If replicated, the current study’s finding of intact default mode Nevertheless, the schizophrenic patients in our study did show activation but failure of de-activation outside the default mode evidence of brain functional abnormality at the whole-brain cor- network in schizophrenia would appear to have two main impli- rected level. Clusters of significant difference were seen in both cations for the pathophysiology of the disorder. The first is that, the memory-evoking v. non-memory evoking cues and in the rather than there being dysfunction of the default mode network memory-evoking cues v. low level contrasts, which took the specifically in schizophrenia, it may be that there is a more general form of relatively greater activation in both cases. As pointed problem with de-activation, which manifests itself in different out by Gusnard and Raichle (2001, see Methods), the interpret- regions (i.e. within or outside the default mode network) depend- ation of relative changes between two active tasks can be difficult, ing on the task used. Just such a proposal has recently been made but the findings in the contrast between autobiographical by Allen et al. (2019), who argue that instead of schizophrenia memory-evoking cues and low-level baseline were clear: they being associated with ‘static’ dysfunctions in the prefrontal cortex represented failure of de-activation in the patients in six of the and the default mode network, in reality the underlying brain dys- seven clusters of significant difference that emerged (the pattern function involves the dynamic balance between the ‘task positive’ in the seventh cluster, in the superior occipital cortex, was one networks (one of which is the fronto-parietal, executive or cogni- of activation in a region where the controls showed neither acti- tive control network) and the ‘task negative’ or default mode vation nor de-activation). All these seven clusters were outside network with which they are normally anticorrelated (Fox et al., the regions usually considered to form part of the default mode 2005). Allen et al. (2019) go on to relate such a dysfunction to Psychological Medicine 127 a change in the balance between the main excitatory and inhibi- Conflict of interest. All authors declare that they have no conflicts of tory transmitters in the brain, glutamate and GABA, although the interest. evidence for dysfunction in the latter of these transmitter systems in schizophrenia is currently slender. Second, the current study’s findings bear on of the issue of References how far default mode network dysfunction might underlie the Allen P, Sommer IE, Jardri R, Eysenck MW and Hugdahl K (2019) Extrinsic cognitive impairment seen in schizophrenia. Anticevic et al. and default mode networks in psychiatric conditions: relationship to (2012) reviewed evidence on the relationship between default excitatory-inhibitory transmitter balance and early trauma. Neuroscience mode network activity and cognitive function in healthy subjects, and Biobehavioral Reviews 99, 90–100. noting that lower default mode network activity has been found to Andreasen NC, O’Leary DS, Cizadlo T, Arndt S, Rezai K, Watkins GL, Ponto LL and Hichwa RD (1995) Remembering the past: two facets of be associated with better performance across a number of cogni- episodic memory explored with positron emission tomography. American tive tasks, and that higher levels of activity are correlated with Journal of Psychiatry 152, 1576–1585. lapses of attention. Based on this they suggested that the relevance Andreasen NC, O’Leary DS, Paradiso S, Cizadlo T, Arndt S, Watkins GL, of default mode network de-activation to cognition in schizophre- Ponto LL and Hichwa RD (1999) The cerebellum plays a role in conscious nia warranted further investigation. So far, however, this investi- episodic memory retrieval. Human Brain Mapping 8, 226–234. gation has been extremely limited. In what appears to be the Anticevic A, Cole MW, Murray JD, Corlett PR, Wang XJ and Krystal JH only study to directly address this question, Ortiz-Gil et al. (2012) The role of default network deactivation in cognition and disease. (2011) examined 18 cognitively impaired and 19 (relatively) cog- Trends in Cognitive Science 16, 584–592. nitively preserved schizophrenic patients during performance of Bado P, Engel A, de Oliveira-Souza R, Bramati IE, Paiva FF, Basilio R, the n-back working memory task. They found that while the cog- Sato JR, Tovar-Moll F and Moll J (2014) Functional dissociation of ventral frontal and dorsomedial default mode network components during resting nitively impaired patients showed hypoactivation compared to the state and emotional autobiographical recall. Human Brain Mapping 35, cognitively preserved patients in the DLPFC and other regions, no 3302–3313. differences in de-activation between the two groups were seen, Beckmann CF, Jenkinson M, Woolrich MW, Behrens TE, Flitney DE, even though the group of patients as a whole showed the expected Devlin JT and Smith SM (2006) Applying FSL to the FIAC data: model- failure of de-activation in the medial frontal cortex. The current based and model-free analysis of voice and sentence repetition priming. study’s finding of intact activation during autobiographical recall Human Brain Mapping 27, 380–391. in schizophrenia adds a further, if currently not entirely clear, Berna F, Potheegadoo J, Aouadi I, Ricarte JJ, Alle MC, Coutelle R, Boyer L, dimension to this debate. Cuervo-Lombard CV and Danion JM (2016) A meta-analysis of autobio- In conclusion, the current study finds no evidence of altered graphical memory studies in schizophrenia spectrum disorder. default mode network function in schizophrenia during perform- Schizophrenia Bulletin 42, 56–66. Boccia M, Dacquino C, Piccardi L, Cordellieri P, Guariglia C, Ferlazzo F, ance of a task which normally activates it, autobiographical recall. Ferracuti S and Giannini AM (2017) Neural foundation of human This finding needs to be viewed in the context of (a) conflicting moral reasoning: an ALE meta-analysis about the role of personal perspec- findings in the only other study to use such a task in schizophre- tive. Brain Imaging and Behavior 11, 278–292. nia; and (b) the current lack of certainty that autobiographical Buckner RL, Andrews-Hanna JR and Schacter DL (2008) The brain’s default recall is associated with de-activation outside the default mode network: anatomy, function, and relevance to disease. Annals of the network in healthy subjects. Further studies using not only auto- New York Academy of Sciences 1124, 1–38. biographical memory but perhaps also other tasks that activate Cabeza R, Prince SE, Daselaar SM, Greenberg DL, Budde M, Dolcos F, the default mode network and, crucially, employing a low-level LaBar KS and Rubin DC (2004) Brain activity during episodic retrieval baseline in order to examine de-activations, would therefore be of autobiographical and laboratory events: an fMRI study using a novel desirable. Some limitations need to be acknowledged. The sample photo paradigm. Journal of Cognitive Neuroscience 16, 1583–1594. Conway MA and Pleydell-Pearce CW (2000) The construction of autobio- sizes we employed were relatively small, and it is possible that acti- graphical memories in the self-memory system. Psychological Review 107, vation differences between schizophrenic patients and controls 261–288. may have emerged if these were larger. The schizophrenic patients Crovitz HF and Schiffman H (1974) Frequency of episodic memories as a were taking antipsychotic medication, and this potential con- function of their age. Bulletin of the Psychonomic Society 4, 517–518. founding factor is not easy to fully address in a study making Cuervo-Lombard C, Lemogne C, Gierski F, Bera-Potelle C, Tran E, comparisons with healthy subjects. We did not measure autobio- Portefaix C, Kaladjian A, Pierot L and Limosin F (2012) Neural basis graphical memory performance in the patients and so there is an of autobiographical memory retrieval in schizophrenia. British Journal of unanswered question about whether and to what extent task Psychiatry 201, 473–480. related activations (and de-activations) were influenced by poor Del Ser T, Gonzalez-Montalvo JI, Martinez-Espinosa S, Delgado-Villapalos C task performance. and Bermejo F (1997) Estimation of premorbid intelligence in Spanish people with the word accentuation test and its application to the diagnosis Supplementary material. The supplementary material for this article can of dementia. Brain and Cognition 33, 343–356. be found at https://doi.org/10.1017/S0033291719003052. Dreher JC, Koch P, Kohn P, Apud J, Weinberger DR and Berman KF (2012) Common and differential pathophysiological features accompany Financial support. This work was supported by CIBERSAM and the comparable cognitive impairments in medication-free patients with schizo- Catalonian Government (2017 SGR 1271 and 2017 SGR 1265). Also by a phrenia and in healthy aging subjects. Biological Psychiatry 71, 890–897. grant from the Ministerio de Ciencia, Innovación y Universidades: Juan de DuPre E, Luh WM and Spreng RN (2016) Multi-echo fMRI replication sam- la Cierva-formación contract (FJCI-2015-25278 to PF-C) and a Research ple of autobiographical memory, prospection and theory of mind reasoning Project Grant (FFI2016-77647-C2-2-P to PS-P). And by the Instituto de tasks. Scientific Data 3, 160116. Salud Carlos III, co-funded by European Union (ERDF/ESF, ‘Investing in Fink GR, Markowitsch HJ, Reinkemeier M, Bruckbauer T, Kessler J and your future’): Miguel Servet Research contract (MSII16/00018 to EP-C), Rio Heiss WD (1996) Cerebral representation of one’s own past: neural net- Hortega contract (CM15/00024 to MM-S), and Research Project Grants works involved in autobiographical memory. Journal of Neuroscience 16, (PI18/00877 to RS, PI18/00880 to PM). 4275–4282. 128 Marta Martin-Subero et al. First MB, Spitzer R, Miriam M and Williams JBW (2002) Structured Clinical Ortiz-Gil J, Pomarol-Clotet E, Salvador R, Canales-Rodriguez EJ, Sarro S, Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition Gomar JJ, Guerrero A, Sans-Sansa B, Capdevila A, Junque C and (SCID-I/P). New York: Biometrics Research, New York State Psychiatric McKenna PJ (2011) Neural correlates of cognitive impairment in schizo- Institute. phrenia. British Journal of Psychiatry 199, 202–210. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC and Palmer BW, Dawes SE and Heaton RK (2009) What do we know about Raichle ME (2005) The human brain is intrinsically organized into neuropsychological aspects of schizophrenia? Neuropsychological Review dynamic, anticorrelated functional networks. Proceedings of the National 19, 365–384. Academy of Sciences U S A 102, 9673–9678. Pomarol-Clotet E, Salvador R, Sarro S, Gomar J, Vila F, Martinez A, Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA and Guerrero A, Ortiz-Gil J, Sans-Sansa B, Capdevila A, Cebamanos JM Calhoun VD (2007) Aberrant ‘default mode’ functional connectivity in and McKenna PJ (2008) Failure to deactivate in the prefrontal cortex in schizophrenia. American Journal of Psychiatry 164, 450–457. schizophrenia: dysfunction of the default mode network? Psychological Gemar MC, Kapur S, Segal ZV, Brown GM and Houle S (1996) Effects of Medicine 38, 1185–1193. self-generated sad mood on regional cerebral activity: a pet study in normal Raichle ME (2015) The brain’s default mode network. Annual Review of subjects. Depression 4, 81–88. Neuroscience 38, 433–447. Gomar JJ, Ortiz-Gil J, McKenna PJ, Salvador R, Sans-Sansa B, Sarro S, Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA and Guerrero A and Pomarol-Clotet E (2011) Validation of the word accentu- Shulman GL (2001) A default mode of brain function. Proceedings of the ation test (TAP) as a means of estimating premorbid IQ in Spanish speak- National Academy of Sciences U S A 98, 676–682. ers. Schizophrenia Research 128, 175–176. Rubin C (ed.) (1996) Remembering our Past: Studies in Autobiographical Gusnard DA and Raichle ME (2001) Searching for a baseline: functional Memory. Cambridge: Cambridge University Press. imaging and the resting human brain. Nature Reviews Neuroscience 2, Salgado-Pineda P, Fakra E, Delaveau P, McKenna PJ, Pomarol-Clotet E and 685–694. Blin O (2011) Correlated structural and functional brain abnormalities in Haatveit B, Jensen J, Alnaes D, Kaufmann T, Brandt CL, Thoresen C, the default mode network in schizophrenia patients. Schizophrenia Andreassen OA, Melle I, Ueland T and Westlye LT (2016) Reduced load- Research 125, 101–109. dependent default mode network deactivation across executive tasks in Schacter DL, Addis DR and Buckner RL (2007) Remembering the past to imagine schizophrenia spectrum disorders. Neuroimage Clinical 12, 389–396. the future: the prospective brain. Nature Reviews Neuroscience 8, 657–661. Hahn B, Harvey AN, Gold JM, Fischer BA, Keller WR, Ross TJ and Schneider FC, Royer A, Grosselin A, Pellet J, Barral FG, Laurent B, Stein EA (2016) Hyperdeactivation of the default mode network in people Brouillet D and Lang F (2011) Modulation of the default mode network with schizophrenia when focusing attention in space. Schizophrenia Bulletin is task-dependant in chronic schizophrenia patients. Schizophrenia 42, 1158–1166. Research 125, 110–117. Hahn B, Harvey AN, Gold JM, Ross TJ and Stein EA (2017) Load-dependent Schurz M, Radua J, Aichhorn M, Richlan F and Perner J (2014) hyperdeactivation of the default mode network in people with schizophre- Fractionating theory of mind: a meta-analysis of functional brain imaging nia. Schizophrenia Research 185, 190–196. studies. Neuroscience and Biobehavioral Reviews 42, 9–34. Harrison BJ, Yucel M, Pujol J and Pantelis C (2007) Task-induced deactiva- Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, tion of midline cortical regions in schizophrenia assessed with fMRI. Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Schizophrenia Research 91, 82–86. Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM and Ino T, Nakai R, Azuma T, Kimura T and Fukuyama H (2011) Brain activa- Matthews PM (2004) Advances in functional and structural MR image tion during autobiographical memory retrieval with special reference to analysis and implementation as FSL. Neuroimage 23(Suppl 1), S208–S219. default mode network. Open Neuroimaging Journal 5, 14–23. Svoboda E, McKinnon MC and Levine B (2006) The functional neuroanat- Kopelman MD, Wilson BA and Baddeley AD (1989) The autobiographical omy of autobiographical memory: a meta-analysis. Neuropsychologia 44, memory interview: a new assessment of autobiographical and personal 2189–2208. semantic memory in amnesic patients. Journal of Clinical and van der Meer L, Costafreda S, Aleman A and David AS (2010) Self-reflection Experimental Neuropsychology 11, 724–744. and the brain: a theoretical review and meta-analysis of neuroimaging stud- Mannell MV, Franco AR, Calhoun VD, Canive JM, Thoma RJ and ies with implications for schizophrenia. Neuroscience and Biobehavioral Mayer AR (2010) Resting state and task-induced deactivation: a methodo- Reviews 34, 935–946. logical comparison in patients with schizophrenia and healthy controls. Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Human Brain Mapping 31, 424–437. Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto-Castanon A, Murray RJ, Schaer M and Debbane M (2012) Degrees of separation: a quan- LaViolette P, Wojcik J, Gabrieli JD and Seidman LJ (2009) titative neuroimaging meta-analysis investigating self-specificity and shared Hyperactivity and hyperconnectivity of the default network in schizophre- neural activation between self- and other-reflection. Neuroscience and nia and in first-degree relatives of persons with schizophrenia. Proceedings Biobehavioral Reviews 36, 1043–1059. of the National Academy of Sciences U S A 106, 1279–1284. Oertel-Knochel V, Reinke B, Hornung A, Knochel C, Matura S, Knopf M, Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, Prvulovic D, O’Dwyer L, Lindner M, Rau A, Hampel H, Haenschel C Roffman JL, Smoller JW, Zollei L, Polimeni JR, Fischl B, Liu H and and Linden DE (2012) Patterns of autobiographical memory in bipolar dis- Buckner RL (2011) The organization of the human cerebral cortex esti- order examined by psychometric and functional neuroimaging methods. mated by intrinsic functional connectivity. Journal of Neurophysiology Journal of Nervous and Mental Disease 200, 296–304. 106, 1125–1165.