SCHRES-06310; No of Pages 4 Schizophrenia Research xxx (2015) xxx–xxx

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Reduced default mode network connectivity in schizophrenia patients Anne Pankow a,⁎,1, Lorenz Deserno a,b,c,1, Martin Walter c,d,f, Thomas Fydrich e, Felix Bermpohl a, Florian Schlagenhauf a,b, Andreas Heinz a a

Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité, Universitätsmedizin Berlin, Germany Max Planck Fellow Group ‘Cognitive and Affective Control of Behavioral Adaption’, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany Department of Neurology, Otto von Guericke University, Magdeburg, Germany d Department of Psychiatry, Otto von Guericke University, Magdeburg, Germany e Department of Psychology, Humboldt-Universität zu Berlin, Germany f Leibniz Institute for Neurobioloy, Magdeburg, Germany b c

a r t i c l e

i n f o

Article history: Received 19 May 2014 Received in revised form 10 March 2015 Accepted 22 March 2015 Available online xxxx Keywords: Schizophrenia Default mode network Functional imaging

a b s t r a c t In the present study, we explored possible alterations in the default mode network (DMN) and its functional connectivity in 41 schizophrenia patients and 42 age-matched healthy controls. Schizophrenia patients displayed reduced activation in the ventromedial prefrontal cortex, left superior temporal gyrus including auditory cortex and temporal pole. Psychophysiological interaction analysis revealed reduced connectivity between left superior temporal gyrus including auditory cortex and the left temporal pole in schizophrenia patients compared to healthy subjects. © 2015 Elsevier B.V. All rights reserved.

1. Introduction The default mode network (DMN) describes a large-scale functional brain network, which is more active during rest periods compared to cognitively demanding tasks (Raichle et al., 2001). While regions of the DMN are involved in a wide range of psychological functions, such as cognitive control and social evaluation (Broyd et al., 2009), simultaneous activation of the DMN has been hypothesized to mediate intrinsic thought and feeling rather than extrinsic stimulus processing and has thus been associated with processing of self-related information (Mason et al., 2007). It has been proposed that misattributed selfreference may ultimately contribute to the development of positive symptoms in schizophrenia (van der Meer et al., 2010; Pankow et al., 2012). There are several studies reporting alterations in DMN activity in schizophrenia patients (for review see Broyd et al., 2009). These studies differ in task design and methodological analysis strategies. For example, DMN activation was assessed during task-interleaved resting periods (taken from blocked designs) or during resting-state using functional magnetic resonance imaging (fMRI, Whitfield-Gabrieli and Ford, 2012). A recent meta-analysis reported reduced resting-state

⁎ Corresponding author at: Department of Psychiatry and Psychotherapy, Charité, Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. Tel.: +49 30 450 517006; fax: +49 30 450 517944. E-mail address: [email protected] (A. Pankow). 1 These authors contributed equally.

connectivity of medial prefrontal and temporal regions in schizophrenia and suggested that these findings are to be linked to disturbed selfreference processing (Kuhn and Gallinat, 2013). In the present study, we compared a rest period versus a working memory challenge during fMRI to explore possible alterations in the DMN and its functional connectivity in schizophrenia patients. 2. Methods and material 2.1. Subjects The study included 41 schizophrenia patients (SZ; ICD-10 and DSM IV; 10 females and 31 males) treated with antipsychotics and 42 agematched healthy controls (HC; 19 females and 23 males). Based on SCID interviews, patients had no other psychiatric axis I disorder (SCID, First et al., 2001). Healthy controls had no psychiatric disorder (SCID, First et al., 2001). The sample was previously published with a focus on working memory dependent effective connectivity (Deserno et al., 2012) and its application to classification and clustering of psychiatric spectrum diseases (Brodersen et al., 2013). For a detailed group description see Supplementary Table S1. 2.2. FMRI data acquisition Imaging was performed on a 1.5 T Scanner (Magnetom Vision Siemens®) with an Echo Planar Imaging (EPI)-sequence (TR = 2600 ms, TE = 40 ms, flip α = 90°, matrix = 64 × 64, voxel size =

http://dx.doi.org/10.1016/j.schres.2015.03.027 0920-9964/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Pankow, A., et al., Reduced default mode network connectivity in schizophrenia patients, Schizophr. Res. (2015), http:// dx.doi.org/10.1016/j.schres.2015.03.027

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A. Pankow et al. / Schizophrenia Research xxx (2015) xxx–xxx

4 mm × 4 mm × 5.5 mm). Head movement was minimized by using a vacuum pad. Twenty-four slices approximately parallel to the bicommissural plane were collected, covering the whole brain. Twenty fMRI volumes were acquired per block: twelve during stimulation and eight during the resting period. 2.3. FMRI paradigm The participants performed a numeric n-back working memory task as used in previous studies (Schlagenhauf et al., 2008). The task contains the ‘0-back’ condition, where the participants had to respond with a button press each time they saw the number zero. In the ‘2-back’ condition the participants had to press a button when the number presented in the current trial equaled the number presented two trials before. During the rest period, the participants were instructed to fixate a cross in the center of the screen. Each block consisted of 22 stimuli containing three targets and was indicated by an instruction cue displayed for 2 s before each block. The stimuli were presented for 500 ms with an intertrial interval of 900 ms. The rest period between the blocks lasted 20.8 s. Stimulation and resting periods alternated within the experiment with a total of six ‘2-back’- six ‘0-back’- and 6 ‘rest’-periods.

which displayed group differences. Based on theoretical work (Northoff and Qin, 2011; Whitfield-Gabrieli and Ford, 2012) and the observed group difference in this study, the left superior temporal gyrus including auditory cortex was defined as the seed region. Individual time-series were extracted at peak coordinates of the group difference in the left superior temporal gyrus for the contrast ‘rest N 2-back’ (-54/-8/6). For the PPI analysis, time series were deconvolved within a Bayesian framework to generate the neural signal. For each subject, a first-level statistical model was estimated, which included the individual's time series of the seed region, the psychological variable (‘rest’ vs. ‘2-back’), and the reconvolved interaction term. The other task conditions (‘0-back’, ‘2-back’ and cue) were also modeled. Between group differences for the contrast images of the interaction term were tested using a two-sample t-test. Based on the a-priori hypothesis, small volume correction was used. Based on previous studies (Andrews-Hanna et al., 2010; Alonso-Solis et al., 2012) the temporal pole is a region of the DMN and plays a pivotal role in self-reference processing (Pauly et al., 2013). The results of the PPI were corrected for a 20 mm sphere around the peak of the group difference in the temporal pole (-38/16/-34). 3. Results

2.4. FMRI data analysis Functional data were preprocessed using SPM8 (http://www.fil.ion. ucl.ac.uk/spm/). Images were motion corrected, normalized to the standard EPI template provided by the Montreal Neurological Institute (MNI), and spatially smoothed with an 8 mm Gaussian kernel. At the first level, ‘rest’-, ‘2-back’- and ‘0-back’-periods were modeled as well as the instruction cue. Realignment parameters were added as nuisance regressors to the design matrix. At the second level, group comparison between schizophrenia patients and healthy control subjects were conducted using a two-sample t-test for the contrast images ‘rest N 2-back’ at p b 0.05 FWE-corrected for the whole brain (see Table 1). 2.5. Psychophysiological interaction The psychophysiological interaction approach (PPI, Gitelman et al., 2003) was used to assess connectivity differences between regions

3.1. FMRI data Across all the participants, ‘rest N 2-back’ revealed the activation in the typical default mode network, containing medial prefrontal cortex and posterior cingulate as well as temporal regions (Fig. 1A, Table 1). Reduced activation in schizophrenia patients compared to controls was present in the ventromedial prefrontal cortex (2/44/-26), left superior temporal gyrus including auditory cortex (-54/-8/6) and temporal pole (-38/16/-34) (Fig. 1B, Table 1). 3.2. Psychophysiological interaction Healthy controls showed stronger rest-related connectivity in comparison to schizophrenia patients between left superior temporal gyrus and the left temporal pole (-26/24/-30, t = 3.86, p = 0.022) (Fig. 1C, Table 1).

Table 1 Peak coordinates of all participants taken together and comparison between the two groups (HC N SZ) for the contras ‘rest N 2-back’ reported at p b 0.05 FWE corrected for the whole brain (peak and cluster-level). Results of the psychophysiological interaction for ‘rest N 2-back’ (HC N SZ) are corrected for 20 mm sphere around group difference peak in temporal pole (-38/16/-34). Anatomical region

All ‘rest N 2-back’ Ventromedial prefrontal cortex Superior medial gyrus Middle cingulate cortex Posterior cingulate Middle/superior temporal gyrus Middle temporal gyrus Middle temporal gyrus Middle temporal gyrus Temporal pole Temporal pole Superior occipital gyrus Lingual gyrus HC N SZ ‘rest N 2-back’ Ventromedial prefrontal cortex Middle/superior temporal gyrus Temporal pole PPI, HC N SZ Temporal pole

Cluster size

MNI-coordinates

R/L

x

y

z

101 33 63 145 82 16 9 7 3 1 5 2

2 −6 −2 −6 −62 58 −58 62 30 −30 −18 14

36 60 −28 −56 −68 −72 −4 0 20 16 −96 −68

−22 30 46 6 22 22 −22 −22 −38 −42 42 −6

32 148 74

−2 −54 −38

44 −8 16

2

−26

24

Peak-level

Cluster-level

T

pFWE-corrected

pFWE-corrected

R L L L L R L R R L L R

7.49 6.16 6.87 8.18 8.58 5.89 5.27 5.19 5.47 4.86 5.03 4.90

b0.001 b0.001 b0.001 b0.001 b0.001 ≤0.001 0.009 0.012 0.004 0.035 0.020 0.031

b0.001 b0.001 b0.001 b0.001 b0.001 ≤0.001 0.004 0.006 0.015 0.028 0.009 0.020

−26 6 −34

L L L

4.82 5.38 4.62

0.041 0.006 0.075

0.232 0.002 0.035

−30

L

3.86

0.022

0.073

Please cite this article as: Pankow, A., et al., Reduced default mode network connectivity in schizophrenia patients, Schizophr. Res. (2015), http:// dx.doi.org/10.1016/j.schres.2015.03.027

A. Pankow et al. / Schizophrenia Research xxx (2015) xxx–xxx

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Fig. 1. Activation pattern of schizophrenia patients and healthy controls (‘rest N 2-back’). All results are presented at 0.001 uncorrected. A: activation of the DMN in both groups. B: healthy controls show elevated activation compared to healthy controls in the ventromedial prefrontal cortex, the left superior temporal gyrus including auditory cortex and the temporal pole. C: healthy controls showed stronger connectivity compared with schizophrenia patients between left superior temporal gyrus including auditory cortex and the left temporal pole.

4. Discussion In the present study, the activations of the core regions of the DMN were reliably detected during rest relative to working memory phases in schizophrenia patients and healthy controls. As interleaved rest periods taken from task-based fMRI designs are well suited for restingstate analyses (Fair et al., 2007), we subtracted task specific activation from interleaved rest periods to control for potentially persisting taskspecific activation patterns during the short resting periods (Heinz et al., 2007). In line with a recent meta-analysis (Kuhn and Gallinat, 2013), the ventral part of the medial PFC, a core region of selfreferential processing (Northoff and Bermpohl, 2004), displayed reduced activation in schizophrenia patients compared to controls. This area has specifically been associated with self-monitoring, valuation processes and self-control (Hare et al., 2009; Murray et al., 2012). However, the meta-analytic results of resting-state studies revealed more regions to be altered in schizophrenia (Kuhn and Gallinat, 2013). This comprised reduced resting-state connectivity in posterior cingulate cortex and precuneus but also increased resting-state connectivity in bilateral lingual gyrus of schizophrenia patients. Outside the cortical-midline areas, we observed diminished activation in the bilateral temporal poles and the left superior temporal lobe. The temporal pole, a region of the DMN, has been associated with understanding other person's behavior in the Theory of Mind tasks (Olson et al., 2007) and self-reference processing (Pauly et al., 2013) which is impaired in schizophrenia (Park et al., 2011). The left superior temporal lobe includes the auditory cortex; aberrant activation in this brain area has been associated with positive symptoms especially auditory hallucinations (Dierks et al., 1999; Hoffman and Hampson, 2011; Northoff and Qin, 2011). Here, we report rest-related functional connectivity between the temporal pole and left superior temporal lobe in schizophrenia patients compared to healthy controls. Disrupted rest-related connectivity between these two brain areas may act at the interface of positive symptoms and social functioning of schizophrenia patients and thereby contribute to the misattribution of inner speech to outside sources in particular self- and other-related information (Karbasforoushan and Woodward, 2012). The limitations of our study are potential effects of neuroleptic medications and gender. Indeed, a longitudinal study in antipsychotic-naive

patients with schizophrenia showed a short-term effect of neuroleptic treatment on regional synchronous neural activity during resting-state (Lui et al., 2010). However, the patients in our sample were mainly chronically ill and long-term medicated. Thus, comparability is limited and future studies are necessary to identify the unique effects of medication and duration of illness. So far, no gender differences have been found with respect to DMN activation in healthy individuals (Filippi et al., 2013). Therefore, an effect of gender on between-group findings seems rather unlikely. One alternative interpretation may suggest that between-group differences in medial PFC reflect deficits of schizophrenia patients in other domains than self-reference, such as cognitive dysfunction (PomarolClotet et al., 2010). However, given the subtraction of interleaved working memory periods, this seems less probable to account for the observed results. Altogether, this study suggests hypoactivation and hypoconnectivity in regions of the DMN implicated in the processing of information related to self and others. Further studies can explore whether reduced functional connectivity between superior temporal gyrus and left temporal pole contributes to altered self-reference processing and acoustic hallucinations. Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.schres.2015.03.027.

Role of funding source The work was supported by a grant from the German Research Foundation (DFG HE2597/4-3&7-3 to AH; DFG SCHL 1968/1-1 to FS) and by the German Ministry for Education and Research (BMBF 01QG87164 & 01GS08159).

Contributors A. Pankow and L. Deserno analyzed the data and contributed to the writing of the manuscript. A. Heinz and F. Schlagenhauf designed the study, supervised the data analyses, and contributed to the writing of the manuscript. M. Walter, F. Bermpohl and T. Fydrich contributed to the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest The authors have declared that there are no conflicts of interest in relation to the subject of this study.

Please cite this article as: Pankow, A., et al., Reduced default mode network connectivity in schizophrenia patients, Schizophr. Res. (2015), http:// dx.doi.org/10.1016/j.schres.2015.03.027

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Acknowledgments We thank Martin Dinges, Michael Koslowski, Dimitri Filonov, and Anne Beck for help during data acquisition.

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Please cite this article as: Pankow, A., et al., Reduced default mode network connectivity in schizophrenia patients, Schizophr. Res. (2015), http:// dx.doi.org/10.1016/j.schres.2015.03.027

Reduced default mode network connectivity in schizophrenia patients.

In the present study, we explored possible alterations in the default mode network (DMN) and its functional connectivity in 41 schizophrenia patients ...
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