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Aberrant intrinsic brain activity and cognitive deficit in firstepisode treatmentnaive patients with schizophrenia Z. He, W. Deng, M. Li, Z. Chen, L. Jiang, Q. Wang, C. Huang, D. A. Collier, Q. Gong, X. Ma, N. Zhang and T. Li Psychological Medicine / Volume 43 / Issue 04 / April 2013, pp 769 780 DOI: 10.1017/S0033291712001638, Published online: 10 August 2012
Link to this article: http://journals.cambridge.org/abstract_S0033291712001638 How to cite this article: Z. He, W. Deng, M. Li, Z. Chen, L. Jiang, Q. Wang, C. Huang, D. A. Collier, Q. Gong, X. Ma, N. Zhang and T. Li (2013). Aberrant intrinsic brain activity and cognitive deficit in firstepisode treatmentnaive patients with schizophrenia. Psychological Medicine, 43, pp 769780 doi:10.1017/S0033291712001638 Request Permissions : Click here
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Psychological Medicine (2013), 43, 769–780. f Cambridge University Press 2012 doi:10.1017/S0033291712001638
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Aberrant intrinsic brain activity and cognitive deficit in first-episode treatment-naive patients with schizophrenia Z. He1,2,3, W. Deng1,2, M. Li1,2, Z. Chen1,2, L. Jiang1,2, Q. Wang1,2, C. Huang1,2, D. A. Collier4, Q. Gong5, X. Ma1,2, N. Zhang6* and T. Li1,2* 1
The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China 3 The Fourth People’s Hospital of Chengdu, Sichuan, China 4 MRC SGDP Centre, Institute of Psychiatry, King’s College London, UK 5 Huaxi MR Research Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China 6 Center for Comparative Neuroimaging (CCNI), Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA 2
Background. Given the important role of the default mode network (DMN) in cognitive function and the wellknown neurocognitive deficit in schizophrenia, it is intriguing to examine systematically the relationship between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia. Method. First-episode, treatment-naive patients with schizophrenia (FES) (n=115) and healthy controls (n=113) underwent resting-state functional magnetic resonance imaging (fMRI) scans and neurocognitive tests. Intrinsic neural activities evaluated by using the fragment amplitude of low-frequency fluctuations (fALFF) and the restingstate functional connectivity assessed by seed-based correlational analysis were compared between patients and controls. Aberrant intrinsic activities and DMN connectivity in patients were then correlated to neurocognitive performance and clinical symptoms. Results. Compared to controls, patients with FES showed decreased fALFF in the bilateral medial prefrontal cortex (MPFC) and the orbitofrontal cortex (OFC), and increased fALFF in the bilateral putamen. Increased functional connectivity with the DMN was observed in the left insula and bilateral dorsolateral PFC (DLPFC) in patients with FES. In patients, aberrant fALFF in the bilateral OFC were correlated with cognitive processing speed ; fALFF in the left OFC and right putamen were correlated with the clinical factors excited/activation and disorganization ; and increased DMN functional connectivity in the left insula was correlated with the clinical factors positive, excited/ activation, disorganization and neurocognitive deficit in the domain of sustained attention. Conclusions. These associations between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia may provide important insights into the neural mechanism of the disease. Received 5 February 2012 ; Revised 27 June 2012 ; Accepted 28 June 2012 ; First published online 10 August 2012 Key words : Cognitive function, fMRI, resting state, schizophrenia.
Introduction Schizophrenia is a serious psychotic disorder characterized by abnormal perception, thought processes and behaviors. Although the pathophysiological mechanism of schizophrenia is unclear, it has been hypothesized that schizophrenia arises from dysfunctional integration of a distributed network of brain * Address for correspondence : Dr T. Li, The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. (Email :
[email protected]) [T. Li] (Email :
[email protected]) [N. Zhang]
regions (Friston & Frith, 1995) or misconnection of neural circuitries, leading to impaired brain function (Venkatasubramanian, 2007 ; Liu et al. 2008 ; Broyd et al. 2009). Therefore, elucidating functional connections between multiple brain regions is important for understanding this disease (Broyd et al. 2009 ; Goghari et al. 2010 ; Rotarska-Jagiela et al. 2010). Abnormal functional connectivity of schizophrenia has been repeatedly reported within a group of brain regions known as the default mode network (DMN) (Liang et al. 2006 ; Liu et al. 2006 ; Bluhm et al. 2007 ; Williamson, 2007 ; Zhou et al. 2007 ; Calhoun et al. 2008 ; Jafri et al. 2008 ; Pomarol-Clotet et al. 2008 ;
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Whitfield-Gabrieli et al. 2009). This network includes the medial prefrontal cortex (MPFC), anterior and posterior cingulate cortex, precuneus, inferior temporal cortex and lateral parietal cortex. The DMN is characterized by elevated coherent spontaneous activation when subjects are at rest, and deactivation when subjects perform cognition-related tasks (Raichle et al. 2001). Although the exact role of the DMN remains to be confirmed, it has been implicated in endogenously generated thought, self-referential activities, monitoring and inner speech (Sonuga-Barke & Castellanos, 2007 ; Williamson, 2007 ; Broyd et al. 2009). Similar alternating patterns between hyper- and hypo-activities has also been observed in another group of brain regions, including the dorsolateral PFC (DLPFC), inferior parietal cortex (IPC) and supplementary motor area (SMA). However, unlike the DMN, these brain regions are more active during cognitive tasks and less active at rest, and thus are collectively called the task-positive network (TPN) (Fox et al. 2005). Of note, activities in the DMN and the TPN are reported to be temporally anticorrelated not only during cognitive tasks but also possibly at rest (Fox et al. 2005). This inverse temporal correlation was interpreted as competition or functional segregation for opposite goals between neural networks. Furthermore, the strength of this anticorrelation was associated with response time in cognitive functions (Kelly et al. 2008) and performance in working memory tasks (Hampson et al. 2010). Taken together, the DMN and the TPN, and the competition (i.e. anticorrelated relationship) between them, are crucial to neurocognitive functions. Increased functional connectivity within the DMN and increased anticorrelation between the DMN and TPN have been reported in patients with schizophrenia (Liang et al. 2006 ; Garrity et al. 2007 ; Zhou et al. 2007 ; Whitfield-Gabrieli et al. 2009 ; Wang et al. 2010a). Increased connectivity within the DMN may reflect excessive attentional orientation to introspective thought and may contribute to disturbances of thought in schizophrenia (Whitfield-Gabrieli et al. 2009). By contrast, increased anticorrelation between the DMN and TPN suggests excessive antagonism between intro- and extrospective psychological processing, and may interfere with the cognitive function of the patient with schizophrenia (Garrity et al. 2007). Consistent with this notion, Garrity et al. (2007) found that the DMN showed greater deactivation when performing cognitive tasks in patients with schizophrenia, and greater deactivation in the medial frontal gyrus and precuneus were correlated with positive symptoms and attentional deficits. Neurocognitive dysfunction, especially in the domains of memory, attention and executive functions,
has been widely reported in schizophrenia and is considered a core feature of the disease (MesholamGately et al. 2009). However, the neural mechanism underlying the cognitive deficit in schizophrenia is still elusive. Given the tight linkage between the DMN and neurocognitive functions and the well-known cognitive deficit in the disease, it is important to examine the relationship between the intrinsic activity/connectivity of the DMN and deficient neurocognitive performance in schizophrenia. Challenges in addressing this issue may exist in two aspects. First, medications used by patients may be a confounding factor. Indeed, atypical antipsychotic drugs have been shown to have significant effects on the brain function of patients with schizophrenia (Snitz et al. 2005). Therefore, it is important to elucidate this relationship in first-episode, treatment-naive schizophrenia (FES) patients to avoid the influence of the chronicity of the illness and the effects of treatment. Second, given the heterogeneity and large inter-patient variance often observed in both imaging and behavioral studies of schizophrenia, a relatively large sample size is necessary. In the present study we have overcome these two challenges by assessing intrinsic activity/ connectivity of the DMN and the performance of a battery of neurocognitive tests in a large group of patients with FES. Based on these measurements, we have explored the relationship between aberrant brain activity/connectivity and neurocognitive function in patients. We have also examined the association between abnormal brain activity/connectivity and the severity of psychotic symptoms.
Method Subjects In total 228 subjects including 115 FES patients (53 males, 62 females) and 113 healthy controls (57 males, 56 females) participated in this study. All patients were recruited at the Mental Health Center of West China Hospital, Sichuan University from August 2005 to October 2010. Healthy controls were recruited from the local area through poster advertisement. Both groups were matched for sex, age and education level. All participants were right-handed based on the Annett Handedness Scale (Annett, 1970). The study was approved by the ethical committee of the West China Hospital of Sichuan University. All patients and controls provided written informed consent. Clinical assessment The patients were interviewed by an experienced psychiatrist using the Structured Clinical Interview for
Intrinsic brain activity in schizophrenia DSM-IV (SCID-P ; First et al. 1997). DSM-IV criteria for schizophrenia or schizophreniform psychosis were used for diagnosis (APA, 1994). Diagnostic results showed 94 patients with schizophrenia and 21 patients with schizophreniform psychosis. Patients diagnosed with schizophreniform psychosis were followed up for at least 6 months and all met the DSM-IV criteria for schizophrenia. Psychopathology associated with schizophrenia was evaluated using the positive and negative syndrome scales (PANSS), which provided the total score and six factor scores including Negative, Positive, Excited/Activation, Anxious/ Depressed, Disorganized and Withdrawn (Van den Oord et al. 2006). All controls were screened with the SCID non-patient version (SCID-NP ; First et al. 1997) for the lifetime absence of psychiatric illnesses. Subjects with organic brain disorders, alcohol and/or drug abuse, pregnancy or any other severe physical illness such as brain tumor or epilepsy were excluded from the study. Magnetic resonance imaging (MRI) data acquisition All participants were scanned using a 3-T MRI system (EXCITE, General Electric, USA). Functional MRI (fMRI) images were obtained using a gradient–echo echo-planar imaging (EPI) sequence [repetition time (TR)/echo time (TE)=2000/30 ms, flip angle=90x, slice thickness=5 mm, no slice gap, in-plane resolution=3.75r3.75 mm2, matrix size=64r64, field of view (FOV)=240r240 mm2, slice number=30]. Each resting-state fMRI scan contained 200 image volumes. During fMRI scanning, participants were instructed to lie still with eyes closed, remain relaxed and refrain from focusing on any particular thought. Data from 20 subjects (11 patients and nine controls) were discarded because of excessive head movement (translational movement >1.5 mm or rotation >1.5x), resulting in a total of 104 patients and 104 controls for further analysis. Neurocognitive assessment A battery of neurocognitive tests was applied in the present study. The immediate and delayed Logical Memory subtest of the Wechsler Memory Scale (Wechsler, 1987) was used to evaluate verbal memory and paragraph recall abilities. The immediate and delayed Pattern Recognition Memory (PRM) test and the Rapid Visual Information Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess visual memory and sustained attention respectively. The Trail Making Test (TMT, parts A and B ; Reitan, 1992) and the Digit Symbol Test (DST) from the Wechsler Intelligence
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Scales (Wechsler, 1981) were used to assess processing speed (Mesholam-Gately et al. 2009). Eighty patients and 72 healthy controls completed all of the neurocognitive tests whereas the other 24 patients and 32 controls only participated in the imaging session. Data processing Preprocessing and statistical analysis of functional images were carried out using the Statistical Parametric Mapping package (SPM5, Wellcome Department for Imaging Neuroscience, London, UK). For each subject, the first 10 image volumes were discarded to allow the fMRI signal to reach a steady state. Initial analysis included slice time correction and realignment. The resulting images were then spatially normalized to the Montreal Neurological Institute (MNI) EPI template in SPM5, resampled to 3r3r3 mm3, and subsequently smoothed with an isotropic Gaussian kernel (full-width at half-maximum=6 mm). Finally, all preprocessed fMRI data were linearly detrended and band-pass filtered (0.01
