Mirror neuron deficit in schizophrenia: Evidence from repetition suppression

SCHRES-06470; No of Pages 6 Schizophrenia Research xxx (2015) xxx–xxx

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Mirror neuron deficit in schizophrenia: Evidence from repetition suppression Nicole Möhring, Christina Shen, Eric Hahn, Thi Minh Tam Ta, Michael Dettling, Andres H. Neuhaus ⁎ Department of Psychiatry, Charité University Medicine Berlin, Germany

a r t i c l e

i n f o

Article history: Received 13 February 2015 Received in revised form 7 July 2015 Accepted 19 July 2015 Available online xxxx Keywords: Hand gestures Event-related potential Repetition suppression Adaptation Mirror neuron system Social cognition

a b s t r a c t Background: Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The mirror neuron system (MNS) serves as an important neuronal basis for social cognitive skills; however, previous investigations on the integrity of MNS function in schizophrenia remain approximate. Methods: We employed a repetition suppression paradigm that allows for measuring neuronal responses to gesture observation and gesture execution. Cross-modal repetition suppression, i.e., adaptation between observe/ execute and execute/observe conditions, was defined as the decisive experimental condition characterizing the unique sensori-motor properties of mirror neurons. Event-related potentials (ERPs) were assessed in 15 schizophrenia patients and 15 matched controls. Results: We isolated an ERP signature of specific adaptation effects to identical hand gestures. Of critical importance, this ERP signature indicated intact intra-modal adaptive pattern, i.e., observe/observe and execute/execute, of comparable magnitude between groups, but deficient cross-modal adaptation, i.e., observe/execute and execute/ observe, in schizophrenia patients. Conclusion: Our data provide robust evidence that pure perception and execution of hand gestures are relatively intact in schizophrenia. In contrast, visuo-motor transformation processes mediated by the MNS seem to be specifically disturbed in schizophrenia. These results unambiguously demonstrate MNS deficits in schizophrenia and extend our understanding of the neuronal bases of social dysfunction in this disorder. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Impaired social cognition is a common feature of schizophrenia associated with functional outcome (Couture et al., 2006; Smith et al., 2014). Deficits of social interaction have been related to mentalizing/ theory-of-mind abilities and empathy, both of which are substantial for social interaction (Corbera et al., 2013; Derntl et al., 2012; Martin et al., 2014). These abilities, in turn, rely on basic social cognitive skills including perception of socially relevant cues like facial expressions and gestures. In contrast to the large literature on face processing in schizophrenia, only few studies focused on processing of gestures and body postures. These studies clearly demonstrate that schizophrenia patients are less accurate in interpreting (Bucci et al., 2008; Thoma et al., 2014) and imitating gestures and body postures (Matthews et al., 2013; Walther et al., 2013a, 2013b). To successfully process gestures and body postures, the recipient needs to understand both movement and meaning, which neuronally intersect in the mirror neuron system (MNS). Mirror neurons are active during both observing and executing an action (Rizzolatti and Craighero, ⁎ Corresponding author at: Department of Psychiatry, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. E-mail address: [email protected] (A.H. Neuhaus).

2004). Based on this sensori-motor property, an internal motor representation of the observed action (e.g., posture/gesture) is generated, linked with a corresponding affective state, or optionally modulated by higher order cognitive processes. Through this automatic mirroring mechanism, social interaction is facilitated by enabling individuals to understand behavior and intentions of others and thus to imitate or to share emotions (Iacoboni, 2005; Rizzolatti and Sinigaglia, 2007). Following that rationale, it is thought that psychiatric disorders that present with impaired social cognition are likely to exhibit a deficient MNS (Buccino and Amore, 2008; Haker and Rössler, 2009). Direct evidence of neurons with mirror properties is possible through invasive measurements only (Mukamel et al., 2010). For comprehensible reasons, there are no systematic studies applying invasive methods for assessing the integrity of the MNS in psychiatric disorders. In healthy subjects, mainly functional magnetic resonance imaging (fMRI) was used to show topographically overlapping activations during action observation and imitation tasks (Molenberghs et al., 2012). Using this non-invasive approach, a recent study of Thakkar et al. (2014) found an altered activation pattern in relevant MNS nodes in schizophrenia. Contrarily, Horan et al. (2014a) reported decreased self-reported empathy in correlation with activity of the inferior frontal gyrus (IFG), but failed to show reduced activity within this classical mirror neuron area in schizophrenia patients. Besides these inconsistencies,

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Please cite this article as: Möhring, N., et al., Mirror neuron deficit in schizophrenia: Evidence from repetition suppression, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.07.035

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demonstrating overlapping activity, can only provide indirect and preliminary evidence, because this approach cannot exclude spatially overlapping, but distinct neuronal populations (Dinstein et al., 2008). Here, the use of repetition suppression (RS) paradigms constitutes a major advance towards unambiguously and non-invasively characterizing MNS function (Chong et al., 2008; Kilner et al., 2009). RS describes the reduction of neuronal activity in response to repeated presentation of the same stimulus, e.g., in a paired stimulus design (GrillSpector et al., 2006). Comparing neuronal response amplitudes to repetitions with non-repetitions then allows for deciding whether the involved neuronal population can be considered sensitive to the repeated stimulus feature. In the mirror neuron context, intra-modal RS effects indicate sensory (observation/observation) or motor (execution/execution) properties, while cross-modal RS (observation/execution; execution/observation) indicates sensori-motor properties that unambiguously characterize mirror neurons (Möhring et al., 2014a), although, as described above, this approach cannot prove the existence of mirror neurons in a strict sense. So far, the RS paradigm has not been adopted for MNS studies in schizophrenia, which is mainly investigated via transcranial magnetic stimulation to test motor cortex excitability (Enticott et al., 2008; Mehta et al., 2014b) and via mu rhythm suppression in electroencephalography (EEG; Horan et al., 2014b; Mitra et al., 2014; Singh et al., 2011). These studies partially contradict each other, e.g., in terms of decreased (Mitra et al., 2014; Singh et al., 2011) versus increased mu suppression in schizophrenia (Horan et al., 2014b), and, even more important, they investigated surrogates of motor cortex function that is – as an effector organ – associated with, but not part of the MNS (Rizzolatti and Craighero, 2004). Here, we applied a cross-modal adaptation protocol to investigate MNS activity in schizophrenia for the first time. Adopting the study protocol of Dinstein et al. (2007), our participants observed or executed gestures of the rock–paper–scissors game. According to our previous normative study (Möhring et al., 2014b), we expected to find evidence of reduced mirror neuron activity in mid-latency event-related potentials (ERPs) as expressed by reduced or absent cross-modal RS effects. Specifically, we focused our analysis on the N190 and the P2 components that have been shown to be sensitive to repetitions in our normative study using the same paradigm (Möhring et al., 2014b).

2. Material and methods 2.1. Subjects Fifteen medicated patients with diagnosis of schizophrenia (11 men, 4 women) and fifteen healthy controls participated in the study. Groups were matched for sex and age (± 2 years). Demographic and clinical data of all participants are summarized in Table 1.

Table 1 Demographic and clinical data.

Age (years) Age range (years) Education (years) IQ Verbal IQ Non-verbal IQ Laterality index Interpersonal reactivity index Perspective taking Fantasizing Empathic concern Personal distress

Schizophrenia (N = 15)

Controls (N = 15)

p

35.60 (7.7) 27–57 14.67 (4.6)

35.40 (7.9) 25–58 17.75 (3.8)

.964 – .054

102.80 (15.1) 109.07 (11.4) 90.67 (14.4)

102.83 (7.5) 112.75 (6.7) 90.67 (14.4)

.994 .291 1.000

17.53 (3.8) 16.33 (4.7) 20.33 (2.3) 14.40 (5.4)

19.46 (3.0) 14.77 (3.1) 19.85 (3.8) 11.85 (5.7)

.136 .295 .706 .216

All values are mean values with standard deviation in parenthesis. Between-group differences were assessed by t-tests for independent samples. IQ, intelligence quotient.

All patients were recruited from the outpatient clinic of the Department of Psychiatry, Charité University Medicine Berlin, Campus Benjamin Franklin. They met DSM-IV criteria and had no psychiatric disorder other than schizophrenia and nicotine abuse/dependence. Exclusion criteria were current drug abuse and history of severe medical or neurological disorder including a history of electroconvulsive therapy. Mean duration of illness was 141.23 ± 72.5 months and mean number of episodes was 2.0 ± 1.1. All patients received atypical antipsychotics with a mean chlorpromazine equivalent of 442.04 ± 407.9 mg/d. None of the patients suffered from extrapyramidal motor side effects due to antipsychotic medication within the last 6 months. Clinical symptom severity was assessed with the Positive And Negative Syndrome Scale (PANSS) for schizophrenia: positive symptoms 15.57 (±4.2); negative symptoms 20.43 (±4.9); and general psychopathology 31.29 (±5.5). Control subjects were recruited via newspaper advertisements. They were screened for mental and physical health by a board certified psychiatrist and were excluded when meeting the criteria of psychiatric disorders according to DSM-IV as determined by semi-structured clinical interviews. Moreover, family history of psychiatric illness, medical or neurological disorders, and current intake of psychotropic drugs led to the exclusion of the study. All participants completed a multiple choice vocabulary test (MWT; Lehrl et al., 1995) and the German performance testing system (LPS; Horn, 1983) to estimate verbal and non-verbal intelligence, respectively. The Interpersonal Reactivity Inventory (IRI; Davis, 1983) was applied for assessing empathic ability. All participants had normal or correctedto-normal vision and where right-handed according to the Edinburgh Handedness Inventory (EHI; Oldfield, 1971). The study protocol was approved by the ethics committee of the Charité University Medicine Berlin, and the study was conducted in accordance with the Declaration of Helsinki and its amendments. All subjects gave written informed consent before participating and received monetary reimbursement for their efforts. 2.2. Experimental design The experiment was carried out in a windowless, dimly lit, electromagnetically shielded, and sound attenuated room. Participants were asked to take a seat in a comfortable chair in front of the screen and to direct their gaze towards the monitor. Standardized instructions were given verbally by the experimenter and visually on the screen. In a training phase comprising 10 trials, participants practiced the task to ensure that they followed instructions correctly. During the whole experimental session, subjects were visually monitored by the experimenter through a window from a neighboring room to control for accurate action execution. Participants were instructed to passively observe static images of a hand forming gestures of the popular rock–paper–scissors game (observation condition) and to actively execute respective hand gestures as soon as imperative stimuli depicting rock, paper, or scissors were displayed (execution condition). Stimuli were presented on a 24 in. monitor with a viewing distance of approximately 60 cm and a visual angle of approximately 15 × 10° for the outer stimulus contour using Presentation (Neurobehavioral Systems, Albany, CA). On a light gray background, three naturalistic photographs of a right male hand forming rock, paper, or scissors symbols were displayed in the observation condition and three realistic pictures of a rock, paper, or scissors served as imperative stimuli in the execution condition. Stimulus duration was 2000 ms. Stimulus presentation was organized in pairs (S1 = adapter stimulus; S2 = test stimulus) with an inter-stimulus interval (ISI) of 500 ms that was identified as optimal for eliciting maximal RS effects (Harris and Nakayama, 2007; Kuehl et al., 2013). Stimulus pairs were evenly distributed across intra-modal, i.e., purely sensory (observe/observe) or motor (execute/execute) repetitions, and cross-modal trials, i.e., repetitions across modalities (observe/execute or execute/observe). Stimulus pairs showed either identical hand figures/objects (categorized

Please cite this article as: Möhring, N., et al., Mirror neuron deficit in schizophrenia: Evidence from repetition suppression, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.07.035

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as repetition trials) or different hand figures/objects (categorized as non-repetition trials). Thus, combining all experimental conditions (repetition/non-repetition × rock/paper/scissors × intra-modal/crossmodal × observation/execution), our paradigm consisted of 24 different types of trials. Inter-trial intervals pseudo-randomly varied between 3000 ms and 4000 ms. Fig. 1 gives an overview of the task. In total, 72 stimuli were presented per block, consisting of 24 repetition trials and 12 non-repetition trials. In total, five blocks were presented, each lasting 5 min. The duration of the experiment was thus approximately 25 min excluding the training phase and short breaks between blocks. 2.3. EEG data acquisition and ERP analysis EEG was recorded with a 64-channel DC amplifier (Advanced Neuro Technology, Enschede, The Netherlands) with a sampling rate of 512 Hz using an elastic cap equipped with 64 average referenced Ag–AgCl electrodes according to the extended International 10/10 system and a ground electrode positioned on the forehead. Additionally, bipolar electrodes were placed on the outer canthus of the left eye to monitor eye movements as well as on the Musculus interosseus between the 2nd and 3rd fingers of the right hand to control for muscle activity during action execution. Electrode impedances were kept below 5 kΩ. Brain Vision Analyzer 2.03 (Brain Products, Munich, Germany) was used for offline analysis. Raw data were notch-filtered at 50 Hz and Butterworth-filtered at 0.1 Hz high-pass and 20 Hz low-pass with 24 dB/octave. Ocular artifacts were corrected with independent component analysis (Jung et al., 2000). After down-sampling to 500 Hz, data was segmented to a length of 1100 ms starting 100 ms before and ending 1000 ms after stimulus onset. Segmentation was performed for each experimental condition (S1/S2; repetition/non-repetition; hand figure/object; modality; and action), resulting in 48 different segments for each EEG file. Hand action conditions were entered into analysis only if EMG amplitude was N50 μV within 100 to 1000 ms following an imperative object stimulus. In the next steps, data were baseline corrected and segments contaminated by artifacts (≥80 μV at any electrode except EMG) were removed. Finally, averages were constructed for each experimental condition. In exploratory butterfly plots (data not shown), adapter stimuli were averaged separately for observation and execution conditions in controls. Only those ERP components were selected for subsequent analyses that were associated with cortical gesture processing in our previous

study, i.e., N190 and P2 (Möhring et al., 2014b). For each ERP component, the latency window was set around the mean corresponding peak of the grand average, separately for the observation and execution condition. To define regions of interest for further analyses, current density scalp maps were used to select those electrodes that were located in the center of gravity of each ERP component. The N190 component was scored at electrodes P7, P8, TP7, and TP8 as the most negative peak within 60 ms around the mean corresponding peak of the grand average, i.e., from 156 ms to 216 ms (observation condition) and from 150 ms to 210 ms (execution condition). The P2 component displayed a broader positivity and was thus quantified at electrodes PO3, PO4, PO5, PO6, PO7, PO8, P3, P4, P5, P6, P7, and P8 within 80 ms around the mean corresponding peak of the grand average, i.e., from 216 ms to 296 ms while observing and from 224 ms to 304 ms while executing.

2.4. Statistical analysis SPSS for Windows version 21.0 (IBM, Armonk, NY) was used for statistical analysis. In a first step, electrodes of interest within each hemisphere were averaged for the N190 and P2 ERP components to avoid circular analyses as outlined by Kriegeskorte et al. (2009). In a second step, repeated measures analyses of variance (ANOVAs) were performed separately for both ERP components. Initial ANOVAs included ‘repetition’ (adapter vs. repeated test stimulus vs. non-repeated test stimulus), ‘hand figure’ (rock vs. paper vs. scissors), ‘modality’ (intramodal vs. cross-modal), ‘action’ (observation vs. execution) and ‘hemisphere’ (left vs. right) as within-subject factors and ‘group’ (schizophrenia vs. control) as between-subject factor, respectively. In a next step, the factor ‘figure’ was removed from analysis after it was confirmed that it neither significantly contributed to any main effect nor any interaction. Thus, final ANOVAs were conducted with a 3 (repetition) × 2 (modality) × 2 (action) × 2 (hemisphere) × 2 (group) design. For all tests, Mauchly's test ascertained that the sphericity assumption was not violated. Partial eta squared (η2) served as an estimator of effect size, i.e., the proportion of data variance accounted for by the statistical model. For all significant main effects and interactions, post hoc t-tests were performed with Bonferroni correction by multiplying the specific p value with the number of comparisons in that specific test. Correlation analysis was done using Pearson correlation. The alpha level was set at p b .05 for all tests. Values are given as mean values with standard deviation in parenthesis, if not explicitly stated otherwise.

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Fig. 1. Experimental design and stimuli. Trials always consisted of adapter (S1) and test stimuli (S2) that were presented for 2000 ms each with an inter-stimulus interval (ISI) of 500 ms. Each trial was followed by an inter-trial interval (ITI) that pseudo-randomly varied between 3000 and 4000 ms. Static images of a hand forming rock, paper, or scissors gestures served as passive stimuli (observe condition). Images of rock, paper, or scissors objects served as imperative stimuli where participants had to execute the corresponding hand gesture (execute condition). Stimulus pairs were categorized as intra-modal trials (observe/observe or execute/execute) or cross-modal trials (observe/execute or execute/observe). Experimental trials were further categorized as repetitions (same hand gesture or object) or non-repetitions (different hand gestures or objects).

Please cite this article as: Möhring, N., et al., Mirror neuron deficit in schizophrenia: Evidence from repetition suppression, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.07.035

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3. Results 3.1. N190 Repeated measures ANOVA of the N190 component revealed significant main effects of ‘repetition’ (F2,56 = 4.837; p = .012; η2 = .147) and ‘action’ (F1,28 = 30.915; p b .001; η2 = .525). The factor ‘repetition’ was driven by a specific adaptation effect, where adapter stimuli (− 3.25 ± 1.4 μV) elicited higher N190 amplitudes than repeated test stimuli (− 2.72 ± 1.4 μV; T29 = − 2.900; p = .007). Similarly, non-repetitions (−3.13 ± 1.3 μV) evoked higher N190 amplitudes than repetitions (T29 = − 2.924; p = .007). Our data hence demonstrate an adaptation effect due to identical stimulus repetition. Subsequent analysis of the main effect ‘action’ showed that passively observing static images of hand gestures (− 3.59 ± 1.6 μV) lead to higher N190 amplitudes than actively executing hand gestures in response to corresponding object stimuli (− 2.48 ± 1.1 μV; T29 = −5.637; p b .001). This is consistent with greater sensitivity of the N190 to body parts than to inanimate objects. 3.2. P2 Omnibus ANOVA of the P2 component revealed a significant main effect of ‘repetition’ (F2,56 = 12.253; p b .001; η2 = .304) and significant interactions of ‘repetition ∗ group’ (F2,56 = 4.204; p = .020; η2 = .131) as well as ‘repetition ∗ modality’ (F2,56 = 9.232; p b .001; η2 = .248). The main effect of ‘repetition’ was based on significantly suppressed P2 responses to repeated test stimuli (4.09 ± 2.1 μV) compared with adapters (4.83 ± 2.1 μV; T29 = − 3.986; p b .001) and with nonrepeated test stimuli (4.74 ± 2.4 μV; T29 = − 5.148; p b .001). Paired t-tests demonstrated that the ‘repetition ∗ group’ interaction relied on a strong RS effect of the P2 in the control group, with significantly lower amplitudes in response to repeated test stimuli (3.55 ± 1.4 μV) compared with both adapters (4.62 ± 1.7 μV; T14 = − 4.742; p b .001) and non-repetitions (4.08 ± 1.8 μV; T14 = − 3.158; p = .007). This effect corresponds to a specific adaptation due to identical stimulus repetition that was absent in schizophrenia (see Fig. 2). Most important within the scope of our study, we obtained a significant interaction of ‘repetition ∗ modality’. Paired t-tests indicated intact specific adaptation effects in intra-modal trials in both groups, as evidenced by comparisons of repetitions with both adapters (controls: p b .001; schizophrenia: p = .024) and non-repetitions (controls:

A

[µV] 6

P2

p = .008; schizophrenia: p b .001). In contrast to the homogeneous results of intra-modal trial analysis, we observed a specific dissociation of neuronal responses in cross-modal trials between groups. In controls, P2 amplitudes in response to repeated test stimuli (3.81 ± 1.3 μV) were significantly reduced compared to adapter stimuli (4.57 ± 1.8 μV; T14 = −3.222; p = .006). In schizophrenia patients, however, no significant differences between adapters (4.97 ± 2.5 μV), repetitions (5.02 ± 2.8 μV), and non-repetitions (5.21 ± 2.8 μV) were found, thus indicating a failure of neuronal adaptation processes in cross-modal trials in schizophrenia. An independent t-test including amplitude differences of adapter stimuli minus repeated test stimuli in cross-modal trials confirmed a significant difference of cross-modal adaptation magnitude between groups (controls: 0.76 ± 0.9 μV; schizophrenia: −.05 ± 1.2 μV; T28 = 2.111; p = .044). No correlation was found between P2 measures and IRI or PANSS scores. 4. Discussion The present study aimed at investigating neurophysiological effects of RS in response to hand gesture observation and execution in schizophrenia. Both schizophrenia patients and control participants exhibited specific adaptation effects in intra-modal trials. This robust RS during observing hand gesture stimuli is well in line with our previous findings (Möhring et al., 2014b). Specific isolation of the neuronal signature and temporal dynamics of MNS activity was based on cross-modal adaptation effects of parietal gesture processing ERPs that should adaptively respond to cross-modal repetitions, i.e., when an action is first observed and then executed and vice versa, to allow for inferring MNS activity. In controls, this cross-modal RS effect was demonstrated, whereas this effect was absent in schizophrenia patients, consistent with a deficient MNS. From a functional perspective, our data is in good agreement with the majority of MNS studies in schizophrenia in general (Mehta et al., 2014a) and with findings of previous electrophysiological studies that reported a motor cortex deficit in terms of excitability and mu wave suppression in schizophrenia in particular (Enticott et al., 2008; Mehta et al., 2014b; Mitra et al., 2014; Singh et al., 2011). Moreover, instead of drawing inferences from surrogates of motor cortex function – such as mu rhythm – about the integrity of the MNS, we provide unambiguous evidence of a deficient MNS in schizophrenia by directly assessing sensori-motor properties that characterize mirror neurons. Our data implicate that disturbed social interaction in schizophrenia is independent of perception, but attributable to deficient visuo-motor transformation

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Fig. 2. Grand averages of the P200 component at electrode position PO3, PO4, PO5, PO6, PO7, PO8, P3, P4, P5, P6, P7, and P8 stratified for the significant main effect of ‘repetition’, i.e., adapter stimuli (black line), repeated test stimuli (red line) and non-repeated test stimuli (blue line). Time frame of the P2 ERP component is highlighted in gray. (A) P2 amplitude modulation in controls. Repetition stimuli lead to significantly reduced amplitudes in the P2 time frame. P2 amplitudes in response to repetitions compared with responses to non-repetitions differ significantly, which indicates a specific adaptation effect. (B) P2 amplitude modulation in schizophrenia patients. Adapters and repetitions do not show significant amplitude differences in the P2 time frame. Significant P2 amplitude differences between repetitions and non-repetitions indicate an irregular repetition enhancement. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Please cite this article as: Möhring, N., et al., Mirror neuron deficit in schizophrenia: Evidence from repetition suppression, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.07.035

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processes in the parietal MNS node (Dinstein et al., 2007; Iacoboni et al., 1999; Möhring et al., 2014b). Functionally, our results can thus be nicely linked to disturbances of the frontoparietal network and of IPL function in schizophrenia that has been linked to impaired sensory integration and body image in schizophrenia (Torrey, 2007; Tu et al., 2013). Temporal dynamics indicates relatively early and therefore automatic deficits in schizophrenia, which is well in line with the automatic nature of visuo-motor transformation processes mediated by the MNS (Heyes, 2011). Especially strategic games like the rock-paper-scissors game applied in this study are thought to elicit automatic imitation (Belot et al., 2013; Cook et al., 2012), which is corroborated and further specified by the ERP modulation reflecting MNS activity in the present study. Crucially and of higher clinical relevance, our data imply that deficient social interaction in schizophrenia is rather an automatic process than under voluntary control, which may impact on clinical intervention strategies by implying effectiveness of training rather than therapy. Our results also nicely complement a recent fMRI study on MNS integrity in schizophrenia that reported inferior parietal hypoactivation in the schizophrenia group (Thakkar et al., 2014) by confirming those results and additionally specifying the temporal course of MNS deficit in the cortical information processing cascade. Some limitations have to be acknowledged. Regarding the paradigm, the probability of a repetition trial was two times higher than the probability of a non-repetition trial, thus inducing an inherent expectation for repetitions. Summerfield et al. (2008) have shown that expectation affects repetition suppression. However, when specifically investigating ERPs, it was also found that expectation neither affected all electrodes nor did it abolish RS effects (Summerfield et al., 2011). Still, a balanced task design would have been favorable to rule out the impact of expectation with greater confidence. Furthermore, we did not specifically control for attention, which is a possible confound, because attention deficits are highly prevalent in schizophrenia (Shen et al., 2014). Instead of a behavioral task, we controlled attention indirectly by monitoring muscle activity of the right hand with EMG. Last, although logical inference seems to allow for concluding that cross-modal sensori-motor repetition suppression taps into MNS function, our paradigm cannot directly prove the existence of mirror neurons in humans or their dysfunction in schizophrenia, which – in a strict sense – can only be achieved by invasive single-neuron recordings. In conclusion, this is the first study applying a gestural RS paradigm to infer sensori-motor properties of mirror neurons in schizophrenia. The data demonstrate differential neuronal responses consistent with mirror neuron activation in healthy subjects and a clear deficit in schizophrenia. This finding contributes to a better understanding of a neuronal mechanism that is likely to contribute to social cognitive deficits in schizophrenia. Intact intra-modal adaptation indicates intact perception of gestural stimuli in schizophrenia; consequently, deficits of non-verbal communication may rather not arise from the perceptual level. Instead, our data in accord with previous studies strongly suggests a failure to establish perceptionaction links and visuo-motor transformation processes within the parietal portion of the MNS. Subsequent research questions, especially to which degree this MNS deficit in schizophrenia is longitudinally correlated with functional outcome and how it may be therapeutically alleviated, remain fascinating topics for future studies.

Role of funding source This work was done without funding.

Contributors The study was conceived and designed by authors AHN and NM. Data were assessed by authors NM and CS. ERP analysis was done by authors NM, EH, and TT. Statistical analysis was done by authors NM and MD. The first manuscript version was written by author NM. All authors contributed to the preparation of final manuscript and take responsibility for its content.

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Conflict of interest There is no conflict of interest, financial or otherwise, related to this work for any of the authors. Acknowledgments The authors wish to thank Emily Brandt for assistance in the early phase of this study and all participants for their efforts.

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Please cite this article as: Möhring, N., et al., Mirror neuron deficit in schizophrenia: Evidence from repetition suppression, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.07.035