Abnormally increased and incoherent resting-state activity is shared between patients with schizophrenia and their unaffected siblings

Schizophrenia Research 171 (2016) 158–165 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Abnormally increased and incoherent resting-state activity is shared between patients with schizophrenia and their unaffected siblings Chang Liu a,f, Zhimin Xue a,b,f, Lena Palaniyappan g, Li Zhou a,f, Haihong Liu c, Chang Qi a,f, Guowei Wu a,f, Tumbwene E. Mwansisya a,d, Haojuan Tao a,f, Xudong Chen a,f, Xiaojun Huang a,f, Zhening Liu a,b,f, Weidan Pu e,f,⁎ a Mental Health Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, People's Republic of China Mental Health Center, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China d College of Health Sciences, University of Dodoma, P.O. Box 395, Dodoma, Tanzania e Medical Psychological Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China f The China National Clinical Research Center for Mental Health Disorders, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, 139 Middle Renmin Road, Changsha, Hunan 410011, People's Republic of China g Departments of Psychiatry, Neuroscience and Medical Biophysics, University of Western Ontario, London, Ontario, Canada b c a r t i c l e i n f o Article history: Received 18 August 2015 Received in revised form 18 December 2015 Accepted 11 January 2016 Available online 21 January 2016 Keywords: Schizophrenia Unaffected sibling Neuronal activity Neuronal synchronization Resting-state a b s t r a c t Background: Several resting-state neuroimaging studies in schizophrenia indicate an excessive brain activity while others report an incoherent brain activity at rest. No direct evidence for the simultaneous presence of both excessive and incoherent brain activity has been established to date. Moreover, it is unclear whether unaffected siblings of schizophrenia patients who share half of the affected patient's genotype also exhibit the excessive and incoherent brain activity that may render them vulnerable to the development of schizophrenia. Methods: 27 pairs of schizophrenia patients and their unaffected siblings, as well as 27 healthy controls, were scanned using gradient-echo echo-planar imaging at rest. By using amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (Reho), we investigated the intensity and synchronization of local spontaneous neuronal activity in three groups. Results: We observed that increased amplitude and reduced synchronization (coherence) of spontaneous neuronal activity were shared by patients and their unaffected siblings. The key brain regions with this abnormal neural pattern in both patients and siblings included the middle temporal, orbito-frontal, inferior occipital and fronto-insular gyrus. Conclusions: This abnormal neural pattern of excessive and incoherent neuronal activity shared by schizophrenia patients and their healthy siblings may improve our understanding of neuropathology and genetic predisposition in schizophrenia. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Psychotic symptoms, including false attribution of perceptual experience to external sources (hallucinations), grossly distorted thinking (delusions), and disorganized speech and behavior, are recognized as a defining feature of schizophrenia (DSM-5) (Association, 2013). It has been widely accepted that schizophrenic psychosis is closely related to disrupted self-generated mental activity at rest (Siegal and Varley, 2002). For instance, paranoid ideas regarding conspiracy may reflect an exaggerated sense of self-relevance. Thus, mental activity occurring during rest, in the absence of cognitive tasks, has been thought to be ⁎ Corresponding author at: Medical Psychological Institute, Second Xiangya Hospital, Central South University, Changsha 41011, People's Republic of China. E-mail address: pulv1128@126.com (W. Pu). http://dx.doi.org/10.1016/j.schres.2016.01.022 0920-9964/© 2016 Elsevier B.V. All rights reserved. relevant to the clinical phenomenology of schizophrenia (Malaspina et al., 2004). In the past, positron emission tomography (PET) and electroencephalography (EEG) have been the most commonly used techniques to investigate the spontaneous neuronal activity (Logothetis et al., 2001) at rest in schizophrenia. These studies have consistently demonstrated metabolic over-activity (Ebmeier et al., 1993; Kaplan et al., 1993; Parellada et al., 1994) and increased resting-state electric activity (Boutros et al., 2008; Knott et al., 2001; Lee et al., 2006) in schizophrenia. Importantly, this resting hyperactivity is associated with psychotic symptoms (Lee et al., 2006) such as reality distortion (Kaplan et al., 1993; Liddle et al., 1992). Recently, the amplitude of low-frequency fluctuations (ALFF) in the blood oxygen level-dependent (BOLD) signal measured by the fMRI has emerged as a consistent marker of spontaneous neuronal activity (Biswal et al., 1995; Logothetis et al., 2001; Raichle, 2006; Yu-Feng et al., 2007). Robust evidence has indicated the C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 involvement of ALFF in various cognitive functions, including reading skills (Xu et al., 2015), conceptual processing (Wei et al., 2012), working memory (Zou et al., 2012), cognitive control and response inhibition (Mennes et al., 2010) and personality traits (Wei et al., 2012). Consistent with the findings using PET and EEG, resting-state fMRI studies applying ALFF have documented abnormally increased activity in various brain regions in schizophrenia (Hoptman et al., 2010; Huang et al., 2010; Yu et al., 2014). The combined evidence from PET, EEG and fMRI studies suggests that exaggerated brain activity at rest may be a potential neural substrate for schizophrenia. Furthermore, numerous resting-state fMRI (Lawrie et al., 2002; Liu et al., 2006; Pettersson-Yeo et al., 2011; Yu et al., 2013) and EEG (Ford et al., 2002, 2008; Gross et al., 2007) studies have revealed schizophrenia as a functional “disconnectivity” disorder, concurring with Blueler's hypothesis of this disorder as mentally “splitting” (Bleuler, 1950). These abnormal functional connections have been documented to be associated with symptoms including hallucinations, delusions, distorted thinking and speech (Lawrie et al., 2002; MacDonald et al., 2005; Yoon et al., 2008). However, most previous studies have examined the synchrony of low-frequency fluctuations (LFFs) between remote brain regions (i.e., functional connectivity, FC). From this approach, no conclusion can be drawn on which region has the primary dysfunction. Recently, regional homogeneity (Reho) reflecting synchrony of LFFs (Zang et al., 2004) within circumscribed brain regions has been applied to evaluate regional brain function. Evidence of reduced Reho in recent resting-state fMRI studies (Liu et al., 2006; Yu et al., 2013) has indicated that the local synchrony of spontaneous neuronal activity is a key neuropathological feature of schizophrenia. Additionally, abnormal Reho has been found to be associated with impaired ability of specific information processing and integration in schizophrenia (Yu et al., 2013). Collectively, the evidence on intensity and synchrony of spontaneous neuronal activity suggests that schizophrenia may be characterized by increased (Boutros et al., 2008; Yu et al., 2014) but incoherent neuronal activity (Liu et al., 2006; Yu et al., 2013) at rest. However, previous studies investigated regional brain function in terms of intensity and synchrony of the LFFs separately; thus, no evidence on both increased amplitude and reduced synchrony of spontaneous neuronal activity in the same dataset of schizophrenia patients has been documented. In this study, we combined the ALFF and Reho on resting-state fMRI data to investigate the intensity and synchrony of spontaneous neuronal activity and expected to observe excessive and incoherent neuronal activity at rest in schizophrenia. Furthermore, a growing body of evidence indicates that schizophrenia is a neurodevelopmental disorder with high heritability (Keshavan et al., 2005; Raedler et al., 1998), suggesting that neural deficits related to psychosis may be present prior to the manifestation of behavioral/ clinical symptoms in the unaffected siblings of patients (Keshavan et al., 2005; Raedler et al., 1998; Weinberger, 1987). Unaffected siblings of schizophrenia share half of their genotype with their ill relatives and are at an 8-fold higher risk for developing schizophrenia than the general population (Sadock and Sadock, 2011). Clinical evidence has consistently demonstrated that unaffected siblings of patients display mild psychotic and cognitive symptoms (Bediou et al., 2007; Chen et al., 2009; Delawalla et al., 2006). Genetic predisposition for schizophrenia may also affect normal brain functions in individuals at high-risk for schizophrenia (Whitfield-Gabrieli et al., 2009b). For example, elevated brain activity and reduced resting-state FC have been found in individuals at risk for schizophrenia (Guo et al., 2014; Howes et al., 2006) and individuals with prodromal symptoms of schizophrenia (Dandash et al., 2013; Howes et al., 2009). Notably, recent studies have showed increased intensity (Tang et al., 2015) and reduced synchrony (Liao et al., 2012) of spontaneous neuronal activity using ALFF and Reho, respectively, in unaffected families of schizophrenia patients. Based on these findings, we hypothesized that excessive and incoherent spontaneous neuronal activity seen in patients would be shared by their unaffected siblings. 159 2. Methods 2.1. Participants The sample in this study includes 27 patients, 27 siblings and 27 healthy participants, with most of the participants coming from the dataset in our prior work (Liu et al., 2010). All participants were righthanded (Annett, 1970). 27 patients, independently diagnosed with schizophrenia (SCZ) based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) Axis I Disorders, Patient Edition (SCID-I/P) (First et al., 1998), were recruited through the Department of Psychiatry, Second Xiangya Hospital of Central South University, Changsha, China. The patients had no history of neurological disorder, severe medical disorder, substance abuse, or electroconvulsive therapy. In addition, each patient had at least one unaffected sibling. In the patient sample, 15 patients were drug naïve, while the others were receiving antipsychotic medications at the time of image acquisition (risperidone [n = 6, 2–5 mg/day], clozapine [n = 1, 200 mg/day], quetiapine [n = 3, 400–600 mg/day], and sulpiride [n = 2, 100– 300 mg/day]). The 27 patients with acute illness were all at the earlystage of schizophrenia (illness duration [Mean ± SD] = 18.32 ± 15.84), including 23 patients with illness duration less than 2 years, 3 patients less than 3 years, and 1 patient less than 5 years. 27 unaffected siblings (SIB) of the schizophrenic patients were recruited such that each patient had a sibling in the present study. The inclusion and exclusion criteria were the same as those for the patients except that the siblings did not meet the DSM-IV criteria for any Axis-I psychiatric disorders. 27 healthy controls (HCs) were recruited from the Changsha city area. The inclusion and exclusion criteria were the same as those for the siblings except that the controls had no firstdegree relatives with a history of psychiatric disorders. All SIB and HCs were well matched with the SCZ in terms of age, gender and years of education. All participants provided their written informed consent to participate in this study. The study was approved by the ethics committee of the Second Xiangya Hospital, Central South University. 2.2. Image acquisition and preprocessing Functional MRI images were collected on a 1.5-T GE Signa Twin speed scanner (General Electric Medical System, Milwaukee, Wisconsin) using a gradient-echo echo-planar imaging sequence. The details on the image acquisition protocol, and preprocessing steps for the fMRI data were presented in the Supplemental Materials Text (S.1) and also described elsewhere (Liu et al., 2010; Pu et al., 2012, 2014). 2.3. ALFF analysis Voxel-wise ALFF maps were calculated for each subject and scan using REST software (http://www.restfmri.net). For a given voxel, the time series were first converted to the frequency domain using a Fast Fourier Transform. The square root of the power spectrum was computed and then averaged across a predefined frequency interval. This averaged square root was termed ALFF at the given voxel (Yu-Feng et al., 2007). The ALFF was the averaged square root of the power in the 0.01 to 0.08 Hz window. Following suggestions from Zang et al. (Yu-Feng et al., 2007), ALFF maps were normalized by the mean within-brain ALFF value for each subject to account for differences in scan intensity units, then smoothed with an 8-mm full width at halfmaximum (FWHM) Gaussian kernel. 2.4. Reho analysis Reho was performed on a voxel-by-voxel basis by calculating Kendall's coefficient of concordance of time series within a cluster of neighboring voxels (see Zang et al., 2004 for details). Here, cubic clusters of 27 voxels were used and the Reho value of every cubic cluster 160 C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 was assigned to the central voxel (Zang et al., 2004). A larger Reho value for a given voxel indicates a higher local synchronization of RS-fMRI signals among neighboring voxels. To minimize the whole brain effect, voxel Reho values were scaled by dividing each subject's value by the mean value of their whole-brain Reho. All of these procedures were performed using DPARSF software (http://www.restfmri.net). 2.5. Statistical analysis The statistical analysis of fMRI data was performed using Statistic Parameter Mapping 8 software (SPM8; www.fil.ion.ucl.ac.uk/spm). Firstly, one-way analysis of variance (ANOVA) was used to compare the differences in ALFF or Reho in the whole brain among three groups (p b 0.001, uncorrected); secondly, by applying the results of ANOVA as mask, post-hoc t-tests were performed between each group pairing using a threshold at p b 0.05 with family-wise error (FWE) correction to examine the dysfunctional patterns of spontaneous neuronal activity in schizophrenia patients and unaffected siblings. Statistical analysis of demographic and clinical data was performed using SPSS 16.0 (SPSS, Inc., Chicago, IL). To compare the differences among the three groups, one-way ANOVA or t-test was used for continuous variables and Chi-square test for categorical variables. Pearson's correlations were calculated for ALFF/Reho values and clinical symptoms, illness duration, and medication. The height threshold of statistical significance was set at p b 0.05. 3. Results 3.1. Demographic and clinical characteristics The characteristics of SCZ, SIB and HCs groups are summarized in Table 1. The three groups had no significant differences in age (F (2, 79) = 0.793, p = 0.696), years of education (F(2, 79) = 0.365, p = 0.456) or gender (χ2 = 0.713, p = 0.700). 3.2. Aberrant Reho in SCZ and SIB compared to HCs For the Reho, one-way ANOVA (puncorrected b 0.001) revealed significant differences in the left middle temporal gyrus (MTG), orbito-frontal gyrus (OFG), inferior occipital gyrus (IOG), calcarine and middle occipital gyrus (MOG), and the right pre-central gyrus (PrCG) and superior temporal gyrus (STG) among the three groups (Supplemental Table S1). Post hoc t-tests (p b 0.05, FWE corrected) showed significantly reduced Reho in the left OFG and IOG (Fig. 1 and Table 2), as well as reduced Reho with a significant trend in the left MTG (p = 0.07), in both SCZ and SIB compared to the HCs. Additionally, reduced Reho in the right PrCG was only found in the SCZ, and increased Reho in the Right PrCG and STG were specifically presented in the SIB compared to the HCs. No significant differences in Reho were observed between SCZ and SIB. There were no significant correlations of Reho values with severity of symptoms, medication dosage or illness duration in SCZ. 3.3. Aberrant ALFF in SCZ and SIB compared to HCs For the ALFF, one-way ANOVA (puncorrected b 0.001) revealed significant differences in the left MTG, OFG and fronto-insular gyrus (FIG), and the right STG and OFG among the three groups (Supplemental Table S1). Post hoc t-tests found significantly higher ALFF in the left MTG, OFG and FIG (Fig. 2 and Table 3) in both SCZ and SIB compared to HCs (p b 0.05, FWE corrected). Meanwhile, higher ALFF in the right STG was presented specifically in SIB (Fig. 2 and Table 3) compared to HCs. No significant differences were found between SCZ and SIB. In addition, there were no significant correlations of ALFF values with severity of symptoms, medication dosage or illness duration in SCZ. 4. Discussion In the present study, we observed that excessive and incoherent regional spontaneous neuronal activity in the left MTG and OFG, along with over-activity in the left FIG and incoherent neuronal activity in the left IOG, were shared between schizophrenia patients and their unaffected siblings. These findings indicate that the excessive and incoherent regional spontaneous neuronal activity at rest may be a potential neurophysiological endophenotype for schizophrenia. Meanwhile, schizophrenia patients specifically demonstrated reduced Reho in the right PrCG, while siblings uniquely exhibited increased ALFF and Reho in the right STG and increased Reho in the right PrCG. The reduced coherence of neuronal activity in the PrCG may be specifically related to the illness itself, while the increased neuronal activity in the STG and increased coherence in the PrCG may have a compensatory role in the unaffected siblings. To our knowledge, this is the first study to report concurrent abnormalities in the amplitude and coherence of spontaneous resting-state neuronal activity in local brain regions in schizophrenia patients and their healthy siblings. 4.1. Shared brain alterations in schizophrenia and siblings Numerous studies applying resting-state functional connectivity approach have revealed a functional “disconnectivity” pattern in schizophrenia patients (Woodward et al., 2011) as well as in unaffected siblings (Meda et al., 2012). Our work adds to the prior evidence of disconnectivity to suggest that neuronal incoherence in the local brain regions in schizophrenia patients is also shared by their healthy siblings. Our observation of incoherence in specific brain regions alongside increased amplitude of neuronal activity in other regions in both patients and their siblings, indicates that genetic predisposition for schizophrenia may be characterized not only by “functional incoherence” but also by exaggerated spontaneous neuronal activity. An interesting observation in this study is the presence of both increased intensity and reduced coherence in the left MTG and OFG in patients and their siblings. Functional and structural alterations in these two regions have been consistently documented in schizophrenia patients (Kanahara et al., 2013; Kumari et al., 2009; Li et al., 2010; Liu et al., 2006; Nakamura et al., 2008; Yu et al., 2014), as well as in Table 1 Demographic and clinical profiles of schizophrenia patients, unaffected siblings and healthy controls. Characteristics (Mean ± SD) Schizophrenia patients (n = 27) Unaffected siblings (n = 27) Healthy controls (n = 27) Analysis F/χ2 P Age (year) Education (year) Sex (male/female) Duration of illness (months) Total score (PANSS) Positive score (PANSS) Negative score (PANSS) General score (PANSS) 25.44 ± 5.92 12.30 ± 2.73 15/12 18.32 ± 15.84 85.78 ± 12.80 21.56 ± 4.92 23.15 ± 5.75 41.30 ± 6.38 25.56 ± 6.44 12.70 ± 2.73 16/11 – – – – – 27.44 ± 7.24 12.96 ± 3.39 18/9 – – – – – 0.793 0.365 0.713 0.696 0.456 0.700 Note: PANSS: positive and negative syndrome scale. 161 C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 Fig. 1. Brain regions with significantly altered regional homogeneity (Reho) in patients and unaffected siblings (height threshold p b 0.05 with FDR correction). A. Upper panel showed the brain regions with altered Reho in siblings and patients respectively, the regions with increased Reho are shown in red, the regions with decreased Reho are shown in blue. The lower panel shows three overlapped regions (the left MTG, OFG and IOG) with reduced Reho between patients (yellow regions) and siblings (red regions). The numbers 1–6 represents the left orbitofrontal gyrus, left middle temporal gyrus, right pre-central gyrus, left inferior occipital gyrus, right superior temporal gyrus, and right pre-central gyrus successively. SCZ = schizophrenia patients; SIB = unaffected siblings; MTG = middle temporal gyrus; OFG = orbito-frontal gyrus; IOG = inferior occipital gyrus. (Kaplan et al., 1993), and reduced functional connectivity from the temporal regions to the frontal cortex was demonstrated to be associated with auditory hallucinations in fMRI studies (Friston and Frith, 1995; Lawrie et al., 2002). The functional abnormalities in OFG have been also found to be related with thought disorder in schizophrenia (Duffau et al., 2005; Mandonnet et al., 2007). The convergent evidence suggests that the excessive and incoherent brain activity in the MTG unaffected siblings (Callicott et al., 2003; Hu et al., 2013). The left MTG is responsible for language (Kiehl et al., 2004) and conceptual processing (Wei et al., 2012), while the OFG is important for social cognition (Chemerinski et al., 2002) and interpreting affective “tone” for the assessment of thoughts and intentions (Berthoz et al., 2006). In schizophrenia patients, increased glucose metabolism in the left temporal gyrus was found to be related with reality distortion in a PET study Table 2 Brain regions with aberrant regional homogeneity in schizophrenia patients and unaffected siblings compared to healthy controls. Brain region Cluster size (voxels) Peak coordinates X SIB b HCs Middle temporal gyrus Orbito-frontal gyrus Inferior occipital gyrus SIB N HCs Superior temporal gyrus Pre-central gyrus SCZ b HCs Orbito-frontal gyrus Inferior occipital gyrus Middle temporal gyrus Pre-central gyrus Statistics Y Cohen's d Z t p FWE, corrected 12 74 18 −48 −39 −6 18 54 −99 −33 0 −6 5.08 6.35 4.26 0.001 8.0 × 10−6 0.01 1.41 1.76 1.18 8 6 51 21 −27 9 69 5.10 4.28 0.001 0.009 1.41 1.19 26 19 3 4 −42 −15 −48 60 57 −102 18 3 −3 −12 −24 36 4.70 4.54 3.51 3.85 0.002 0.004 0.076 0.030 1.30 1.26 0.97 1.07 Notes: SCZ = schizophrenia patients; SIB = unaffected siblings; HCs = healthy controls; x, y, z, coordinates of primary peak locations in the Montreal Neurological Institute (MNI) space. 162 C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 Fig. 2. Brain regions with significantly altered amplitude of low-frequency fluctuations (ALFF) in patients and unaffected siblings (height threshold p b 0.05 with FDR correction). B. Upper panel shows the brain regions with increased ALFF in siblings and patients respectively, and the lower panel shows three overlapped regions (the left MTG OFG, and FIG) with increased ALFF between patients (yellow regions) and siblings (red regions). The numbers 1–4 represents the left orbito-frontal gyrus, fronto-insular gyrus, middle temporal gyrus, the right superior temporal gyrus respectively. SCZ = schizophrenia patients; SIB = unaffected siblings; MTG, middle temporal gyrus; OFG, orbito-frontal gyrus; FIG, fronto-insular gyrus. 2008). Our prior work has provided convergent evidence for structural and functional alterations in the FIG, which are consistently correlated with hallucinations in patients in the early-stage of schizophrenia (Pu et al., 2012). Collectively, these findings suggest that FIG dysfunction is implicated in the pathophysiology of schizophrenia, especially for hallucinations (Hoffman et al., 2008; Palaniyappan and Liddle, 2012), and is associated with the genetic risk for this disorder. The IOG is commonly regarded as a key region responsible for visual processing and face perception (Onitsuka et al., 2006) that has been found impaired in schizophrenia. IOG dysfunction is reported to be associated with disorganized symptoms in schizophrenia (Uhlhaas et al., 2006). Moreover, a and OFG observed in this study may play an important role in the neuropathology of psychotic symptoms in schizophrenia. We also found increased ALFF in the left FIG and reduced Reho in the left IOG in both patients and their siblings. The FIG, as a core region for the Salience Network, has been proposed to serve a critical role in the awareness of and attention direction to salient information in humans (Craig, 2002). FIG abnormalities have been reported in patients with schizophrenia (Palaniyappan and Liddle, 2012; Pu et al., 2012), populations at high-risk for developing schizophrenia (Chan et al., 2011; Takahashi et al., 2009) and individuals with prodromal symptoms who later develop frank psychosis (Borgwardt et al., 2008; Glahn et al., Table 3 Brain regions with aberrant amplitude of low-frequency fluctuations in schizophrenia patients and unaffected siblings compared to healthy controls. Brain region Cluster size (voxels) Peak coordinates Statistics Cohen's d X Y Z t p FWE, corrected SIB N HCs Middle temporal gyrus Orbito-frontal gyrus Fronto-insular gyrus Superior temporal gyrus 6 5 7 12 −60 −39 −42 42 −54 48 24 −36 12 −6 −6 12 4.47 3.70 4.27 5.24 0.002 0.024 0.004 0.0002 1.24 1.03 1.18 1.45 SCZ b HCs Orbito-frontal gyrus Fronto-insular gyrus Middle temporal gyrus 31 8 18 −39 −42 −51 51 48 -21 15 -9 -12 4.67 4.60 4.57 0.001 0.002 0.002 1.30 1.28 1.27 Notes: SCZ = schizophrenia patients; SIB = unaffected siblings; HCs = healthy controls; x, y, z, coordinates of primary peak locations in the Montreal Neurological Institute (MNI) space. C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 resting-state fMRI study from our lab also found reduced Reho in the IOG in schizophrenia patients (Liu et al., 2006), and the present study adds evidence that incoherent activity of the IOG is also presented in the patients' unaffected siblings. The excessive and incoherent neuronal activity shared by patients and their siblings may serve as a candidate for a neurophysiological endophenotype of schizophrenia. Firstly, all of the brain regions observed to be functionally altered in both patients and their siblings have been implicated in the neuropathology of psychotic symptoms in schizophrenia. Secondly, direct evidence from genetic-imaging studies has indicated that the structural or functional alterations in these brain regions are associated with risk genes for schizophrenia, such as ZNF804A (Donohoe et al., 2011; Kuswanto et al., 2012; Nenadic et al., 2015; Walter et al., 2011), neuregulin 1 (Addington et al., 2007), and DAOA Arg30Lys (Schultz et al., 2011), and DCDC2 (Jamadar et al., 2011). For example, previous studies have documented significant associations between ZNF804A genetic variants and gray matter loss of the OFG (Nenadic et al., 2015) and insula (Donohoe et al., 2011), as well as between ZNF804A variants and the gray matter volume (Nenadic et al., 2015), white matter integrity (Kuswanto et al., 2012; Wassink et al., 2012) and brain activation (Walter et al., 2011) of the temporal cortex in schizophrenia patients. So far, however, no studies have examined the relationship between genetic variation and spontaneous neuronal activity, which needs to be clarified. 4.2. Unique brain alterations in schizophrenia and siblings This study found that while schizophrenia patients specifically demonstrated reduced Reho in the right PrCG, siblings uniquely exhibited increased Reho in the left PrCG, as well as increased ALFF and Reho in the right STG. The PrCG, traditionally regarded as a core region of the dorsal attention network, sub-serves the top-down attentional control which relates to various cognitive functions in human (Noudoost et al., 2010). Interestingly, our data showed that the coherence of neuronal activity in the PrCG was reduced in schizophrenia patients, but increased in siblings. This finding concurs with the clinical phenomenon that patients suffer more severe cognitive impairments compared to their healthy relatives (Boos et al., 2007). Consistently, previous studies have also reported decreased Reho in this region in schizophrenia patients (Liu et al., 2006; Yu et al., 2013). We propose that while the reduced neuronal coherence in the PrCG may be more related to the illness itself, the increased coherence in this region may compensate for the attenuated cognitive functions in healthy siblings (Delawalla et al., 2006). The STG, similar to the MTG, is also mainly involved in language processing (Redcay, 2008) in healthy subjects. In schizophrenia, gray matter loss and functional disconnectivity, as well as inefficient activation during tasks in this region have been consistently documented to be related with hallucinations (Lawrie et al., 2002; Matsumoto et al., 2014; Woodruff et al., 1997). Interestingly, this study found that increased ALFF and Reho in the right STG was presented in unaffected siblings, but not in patients. Given the evidence of the correlation between STG hypoactivity and hallucinations in schizophrenia patients, the STG hyperactivity (increased intensity and coherence of spontaneous neuronal activity) observed in unaffected siblings may reflect a compensatory role providing resilience to hallucinations. 4.3. Strengths and limitations In this study, we have highlighted the importance of spontaneous neuronal activity at rest in the neuropathology of and genetic susceptibility to schizophrenia, and thus point to excessive and incoherent neuronal activity as a potential endophenotype for examining genetic diathesis for this disorder in the future. Interestingly, in an overlapping dataset, we have previously observed increased connectivity within default-mode network, shared between patients and siblings using a seed-based approach to measure distributed (rather than local) 163 connectivity (Liu et al., 2010). The presence of increased activity and reduced regional coherence observed in the current study, along with the increased distal connectivity within the DMN observed previously in this sample, adds support to the presence of widespread disorganization in the brain activity in schizophrenia. In particular, the presence of such aberrations within the DMN regions supports the primacy of disturbances in self-processing in schizophrenia (Whitfield-Gabrieli et al., 2009a). Moreover, our prior work (Pu et al., 2014) found that the brain circuits mainly related to negative symptoms and volition deficit were impaired in both neuroleptic-treated and neuroleptic-naïve schizophrenia patients, and that the circuits mainly related to positive symptoms were altered in untreated patients, but not in treated patients. The findings by Pu et al. suggest that current pharmacological treatment may mainly influence the brain circuits implicated in positive symptoms, but not those involved in negative symptoms. In the present study, however, we found no significant correlations between the medications and the increased ALFF or reduced Reho in patients. One possible explanation is that our study only recruited 12 patients on antipsychotic treatment who were included in the correlation analysis, so the relatively small sample may degrade the statistical power in the correlation analysis. Another possibility is that current pharmacological treatment has no effect on the increased ALFF and reduced Reho in schizophrenia. To better clarify this issue, we compared the ALFF and Reho values in treated patients and drug-naive patients to healthy controls (p b 0.05, FDR correction) respectively (Supplemental Tables S2, S3), and found that both patient groups demonstrated increased ALFF and decreased Reho in similar brain regions (specifically located at the OFG and MTG). Several limitations necessitate caution when interpreting the results of this study. Firstly, our relatively small sample may degrade the statistical power in the behavioral correlation analysis, which showed no significant associations between the severity of symptoms and ALFF or Reho in patients. However, consistent with our findings, previous studies (Hoptman et al., 2010; Liu et al., 2006) applying ALFF or Reho separately in schizophrenia found no significantly behavioral correlations either. Thus, another possible explanation is that the amplitude and synchrony of spontaneous neuronal activity could be used qualitatively to help locate functional alterations, but not as a quantitative marker for evaluating schizophrenia symptoms. Nevertheless, future studies using larger samples are needed to clarify the relationship of the increased intensity and reduced synchrony of local brain activities with psychotic symptoms in schizophrenia. Secondly, although previous studies have consistently demonstrated that unaffected siblings of schizophrenia display mild psychotic and cognitive symptoms (Bediou et al., 2007; Chen et al., 2009; Delawalla et al., 2006), we did not measure the degree of clinical symptoms in the siblings. As a result, the relationship between subtle speech and behavioral disorganization in siblings and the reported brain abnormalities of incoherence and excess activity was not tested in our study. Finally, owing to the cross-sectional design, we cannot conclude the exact progressive features of these shared brain alterations in siblings and patients. Future longitudinal studies may help provide further insight into how the shared brain alterations progress from the at-risk state for developing psychosis to the discrete illness. 5. Conclusion In summary, the present study suggests that schizophrenia and their unaffected siblings share increased and incoherent neuronal activity in local brain regions related to language processing, social cognition and emotion-related functioning and visual processing. Our findings regarding these common brain abnormalities observed in schizophrenia and their siblings may offer a framework for examining effects of genetic diathesis on the development of schizophrenia. Conflict of interest The authors declare no conflict of interest. 164 C. Liu et al. / Schizophrenia Research 171 (2016) 158–165 Contributions Dr Pu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Weidan Pu designed the study. Chang Liu and Weidan Pu analyzed, interpreted the data and wrote the first draft of the manuscript. Zhimin Xue and Zhening Liu provided fMRI technical support and revised it critically for important intellectual content. Lena Palaniyappan revised it critically for important intellectual content. Zhimin Xue, Li Zhou, Haihong Liu, Chang Qi, Guowei Wu, Tumbwene E. Mwansisya, Haojuan Tao, Xudong Chen, Xiaojun Huang collected the data. All authors contributed to and have approved the final manuscript. Role of funding source This work was supported by the National Natural Science Foundation of China (81401125 to W.P., 81271485, 81471362 and 81561168021 to Z.N. Liu, 81171287 to Z.X.) and Hunan Provincial Innovation Foundation for Postgraduate (CX2014B106). Acknowledgment We thank Zhong He, the Second Xiangya hospital, Central South University, for his assistance in fMRI data acquisition. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2016.01.022. 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