Advances in neuroimaging research of schizophrenia in China

Dengtang LIU*, Yifeng XU, Kaida JIANG

?Review?

Advances in neuroimaging research of schizophrenia in China

Dengtang LIU*, Yifeng XU, Kaida JIANG

schizophrenia, magnetic resonance imaging, magnetic resonance spectroscopy, diffusion tensor imaging, China

Neuroimaging studies of schizophrenia include both structural and functional techniques.[1-3]The former include X-ray computed tomography (CT) and magnetic resonance imaging (MRI); the latter include singlephoton emission computed tomography (SPECT), positron emission tomography (PET), functional MRI (fMRI),and magnetic resonance spectroscopy (MRS).[1-12]Diffusion tensor imaging (DTI) is another functional technique that measures the structure and integrity of the white matter.[13,14]This review describes the evolution of the use of these techniques in the study of schizophrenia(not including molecular neuroimaging) from the perspective of the results generated by researchers in mainland China.

1. Structural neuroimaging studies of schizophrenia

Since the end of the 19th century, researchers seeking the biological basis of schizophrenia have focused on the structure and function of the brain. The earliest study may be the 1879 report by Crichton-Browne that the brains of deceased individuals with schizophrenia were lighter than those of individuals with mood disorders but heavier than those of individuals with dementia. This was followed by a series of neurological autopsy studies and neuropathology studies.[1,2]Pneumoencephalography was the earliest form of in vivo neuroimaging. In 1927, Jacobi and colleagues used pneumoencephalography and found enlarged ventricles and hydrocephalus among individuals with schizophrenia, the first report of structural changes associated with schizophrenia.[1,2,15]

The first contemporary brain structure study of schizophrenia was conducted in 1976 by Johnstone and colleagues[16]who assessed 17 individuals with schizophrenia using CT and found enlarged lateral ventricles and cortical encephalatrophy. Additionally,they found that the enlargement of the lateral ventricles was associated with cognitive impairment but unrelated to antipsychotic treatment.[16]The earliest CT study in China by Yu and colleagues in 1983[17]found that 30%of individuals with schizophrenia had encephalatrophy.A replication study by Wang and colleagues reported in 1986[18]also documented enlarged ventricles and widened sulus. The number of CT studies on schizophrenia in China grew significantly after 1987.[19-22]A 10-year follow-up study of their original sample by Wang and colleagues[23]found that the prevalence of encephalatrophy inthe patients had risen from 16 to 31% over the 10-year interval; they concluded that the structural abnormalities in schizophrenia were related to the duration of disease.

Table 1 lists MRI studies on schizophrenia in China.Early studies engaged relatively simple imaging sequences and low-frequency magnetic fields. The analysis and presentation of the results were relatively basic.They reported that approximately 30% of individuals with schizophrenia had encephalatrophy, which was identified as reduced volume of the brain, widened sulus, and enlarged third and lateral ventricles.[24-30]The emergence of high fields MRI (e.g., 3T) and voxel-based morphometry (VBM) in 2006 equipped researchers with improved technology that could objectively quantify the volume and density of the local gray matter. Using VBM, a series of studies in China found reductions in the gray matter in the frontal lobe, temporal lobe and its interior structures, anterior cingulate, insula, parietal lobe, and cerebellum,[31-38]results that were consistent with findings from other countries. For example,Williams reviewed MRI-VBM studies and concluded that major structural brain changes in chronic schizophrenia included decreased gray matter in the superior temporal lobe (reported by 81% of studies) and in the inferior frontal lobe, inferior frontal lobe, inferior temporal lobe, and insula (reported by 50 to 70% of studies).[39]In first-episode schizophrenia reductions of the gray matter in the anterior cingulate gyrus and in the right parietal lobe were reported by 15 to 25% of studies and reductions of the gray matter in the inferior frontal lobe and the medial prefrontal lobe were also reported.[39]After two to three years of follow-up of first-episode schizophrenia, progressive reductions of the gray matter in the prefrontal-temporal lobe were found, changes that converge with those seen among individuals with chronic schizophrenia.[39]

2. Functional neuroimaging studies of schizophrenia

2.1 Functional magnetic resonance imaging (fMRI)studies

Liu and colleagues discussed the use of MRI in psychiatric research in 2001[8]and conducted a series of studies on cognitive functioning among Chinese individuals without mental disorders.[40-42]In 2002, they reported results from a fMRI study on schizophrenia which found that treatment with antipsychotic medications(risperidone or chlorpromazine) can activate certain brain areas among patients with schizophrenia.[9]

Table 2 lists task-based fMRI studies on schizophrenia from China. Tasks used in these studies included basic cognitive functioning (e.g., working memory,[10,43,45,47,48-52]verbal functioning,[9,44]and executive functioning[46]) and social cognitive functioning(e.g., face recognition[48]). These studies found that patients with schizophrenia had impairment in the memorization of active information as well as in the management and execution of active information.[10,43,45,47,48-52]The Sternberg item recognition task is one of the most widely used tests for short-term memory; studies that use this test in conjunction with fMRI report that during the maintenance stage of the task individuals with schizophrenia had increased activity levels in the left motor cortex, dorsolateral prefrontal cortex (DLPFC),ventral prefrontal cortex (VPFC), and the right precuneus– this suggests reduced efficiency of these brain regions.[10,43-45]The n-back task is a commonly used task to evaluate the ability to manage and execute working memory; based on the results of this task, individuals with schizophrenia were found to have impairment in the prefrontal cortex.[47]The Stroop task evaluates selective attention and impulse control; using this test, distracted individuals with schizophrenia were found to have deactivation in the left middle frontal gyrus and the right anterior cingulate and increased activity in the temporal lobe and right superior frontal lobe.[46]Using the facial recognition task, which evaluates social cognitive function, individuals with schizophrenia exhibited deactivation of the bilateral fusiform gyrus, occipital gyrus, cingulate gyrus, middle frontal gyrus, inferior frontal gyrus and cerebellum, left superior frontal gyrus, superior parietal lobe and the thalamus, and the right inferior parietal lobe.[48]Using the Burke dysphagia screening test, Jiang and his team found that after eight weeks of treatment with risperidone (3.8 mg/d), patients with schizophrenia showed improved brain activities in the left superior frontal gyrus and the left VPFC; this suggests that antipsychotics can ameliorate defective working memory in schizophrenia.[10]

Resting-state fMRI (as opposed to task-based fMRI)refers to fMRI conducted under a completely relaxed state. Under the resting state, certain areas of the brain are actively performing important functions.[53]Liu and colleagues found decreased regional homogeneity in individuals with schizophrenia in the bilateral frontal lobes, temporal lobes, inferior cerebellum, right parietal lobe, and the left limbic lobe.[54]Jiang and colleagues studied a sample of individuals with early-onset schizophrenia (12-19 years of age) and found lower regional homogeneity in the bilateral medial prefrontal cortex (MPFC).[55]More recently, researchers used the amplitude of low frequency fluctuations (ALFF) to evaluate resting-state brain functions and found that among individuals with schizophrenia the ALFF was elevated in the right corpus callosum, occipital lobes, leftcerebellar lobe, superior frontal gyrus and precuneus,and the ALFF was decreased in the bilateral postcentral gyrus and left precuneus.[56]Huang and colleagues reported lower ALFF at the MPFC and higher ALFF at the bilateral putamina among those with drug-na?ve schizophrenia.[57]The above studies provide supportive evidence about the role of a dysfunctional MPFC in the pathogenesis of schizophrenia. Lui and colleagues investigated the influence of antipsychotics on restingstate brain functions among patients with schizophrenia and found that after six weeks of treatment with atypical antipsychotic medications, patients with firstepisode schizophrenia showed higher ALFF at the

bilateral prefrontal cortex, parietal lobe, left superior temporal lobe, and the right caudate; moreover, this increase of ALFF was correlated with improvement of clinical symptoms.[58]

Table 1. Magnetic resonance imaging(MRI) studies of schizophrenia in China

Table 2. Task-based functional magnetic resonance imaging(fMRI) studies of schizophrenia in China

2.2 . Magnetic resonance spectroscopy (MRS) studies

Dopamine (DA) hyperfunction is an important hypothesis in the etiology of schizophrenia. It has been challenged in recent years due to the limited effectiveness of antipsychotic medications on negative symptoms and impaired cognition.[59]In its place the glutamate hypothesis has gained in popularity because it not only accounts for psychotic symptoms but it can provide a sensible explanation for the defective cognition in schizophrenia. This hypothesis postulates that individuals with schizophrenia have deactivated N-methyl-D-aspartic acid (NMDA) receptors, which results in a deficiency of gamma-aminobutyric acid(GABA) and disinhibition of glutamic acid. Some scholars consider the hyperfunction of DA a result of the deficiency of GABA.[59,60]Assessment of the glutamate hypothesis requires accurate measurement of GABA in the brains of individuals with schizophrenia.Magnetic resonance spectroscopy (1H-MRS) is the most common technique for measuring the level of GABA in combination with high-frequency (≥3T) MRI.[61,62]

Table 3 lists MRS studies in China which have been used to assess levels of N-acetylaspartic acid(NAA), creatine (Cr), and choline (Cho) in individuals with schizophrenia.[63-68]They have found a decreased NAA/Cr ratio in the prefrontal cortex among patients with schizophrenia.[64-67]Most studies found no significant changes in the Cho/Cr ratio,[64-66]but Gao and colleagues reported a decreased Cho/Cr ratio in the bilateral frontal cortex.[67]These findings support hypotheses about the early damage of neurons in the frontal cortex of individuals with schizophrenia. There have been contradictory results from MRS studies of the hippocampus: Wang and colleagues[63]found an increased Cho/Cr ratio but no changes in the NAA/Cr ratio among male patients with schizophrenia while Peng and colleagues[65]found a decreased NAA/Cr ratio among patients with first-episode schizophrenia. Chen and colleagues[64]explored the effect of antipsychotics on brain metabolism but found no changes in the NAA/Cr or CHO/Cr ratios at the bilateral frontal cortex with treatment, suggesting that short-term treatment with atypical antipsychotic medications may not affect metabolism in the frontal cortex.

2.3 Diffusion tensor imaging (DTI) studies

DTI, which produces images of brain white matter and fiber tracts, highlights structural and functional asymmetry in different parts of the brain. Normally both grey matter and white matter are asymmetric,[1,2]but several researchers have found that in schizophrenia the asymmetry is reduced or reversed. Wang and colleagues[70]found that the asymmetry of the anterior cingulate tract was reduced in patients with schizophrenia. Su and colleagues[80]found that the asymmetry of the bilateral frontal lobe disappeared inpatients with schizophrenia and that the laterality of the genu and the posterior limb of the internal capsule was reversed.

Table 3. Magnetic resonance spectroscopy (MRS) studies on schizophrenia in China

DTI research has found structural abnormalities in the corpus callosum of patients with both firstepisode and chronic schizophrenia. Most research on the corpus callosum of patients with schizophrenia reports decreased fractional anisotropy (FA) in the genu,[79,80,83,86]and some studies report abnormalities in the splenium[73,76,86]and the truncus[74,86]of the corpus callosum. Kong and colleagues[83]found a reduced FA value in the genu of chronic patients but not in firstepisode patients, suggesting that the abnormality in that area reflects progression of the disease. Li and colleagues[86]compared five areas of the corpus callosum (splenium, truncus, anterior genu, mid genu,and posterior genu) in patients with schizophrenia,patients with bipolar disorder, and healthy controls;they found that both patient groups had lower FA values in all areas than those of healthy controls but they did not differ significantly from each other—which suggests that abnormalities in the corpus callosum are a shared component in the pathogenesis of schizophrenia and bipolar disorder.

The internal capsule has also been extensively studied. The first study in China by Zhao and colleagues[72]did not find any abnormalities in the internal capsule of patients with schizophrenia but subsequent studies reported reduced FA in the anterior limb of the bilateral internal capsule,[75,80]anterior limb of the left internal capsule,[77]genu of the left internal capsule,[80]and genu of the right internal capsule.[84]

Other studies report changes in the white matter and fiber tracts in other brain regions including the cerebellar peduncle, cingulate tract, cerebral peduncle,corona radiate, frontal lobe, temporal lobe, parietal lobe, insula, hippocampus, frontotemporal junction,parieto-occipital fasciculus, longitudinal fasciculus,and external capsule.[69-73,76,78,80-82,84-85]The results of DTI studies about schizophrenia conducted in China are summarized in Table 4.

2.4 Brain network

Brain network is currently a popular field in brain imaging research of schizophrenia in China.[87,88]Structural brain network research employs MRI to assess complex structural human brain networks and DTI to assess the white matter fiber tracts that connect these networks.Functional brain network research employs resting-state fMRI, task-state fMRI, electroencephalography (EEG),and magnetoencephalography (MEG) to assess complex functional human brain networks.[87-91]

2.4.1 Structural brain network

In 2012, Zhang and colleagues[92]used structural MRI to collect morphological data of the brain, and used the Automated Anatomical Labeling atlas (ALL) template to divide the brain into 78 areas (nodes). They used the graph theory analytical method for complex networks to analyze the brain network based on the thickness of the cortices. They found that the ‘small world’ property of the brain network of patients with schizophrenia was abnormal: (a) compared to normal brains the characteristic path length and the clustering coefficient increased; (b) the nodes in some brain areas had decreased centrality and thinner cortices (especially the left parahippocampal gyrus, inferior temporal gyrus,angular gyrus, and right superior frontal gyrus, which are part of the default network); and (c) the nodes in other brain areas had increased centrality, including nodes in the primary cortex (bilateral precuneous, left precentral gyrus, postcentral gyrus, and right Heschl gyrus) and the paralymbic system (bilateral orbital frontal gyrus,temporal pole, right cingulate tract, and inferior parietal gyrus). These findings indicated that the characteristics of the topology of the brain network changed in patients with schizophrenia. In 2014, Zhang and colleagues[93]reported that patients with schizophrenia had decreased connectivity between the thalamus and the bilateral inferior frontal gyrus, left superior temporal gyrus, and right parieto-occipital regions. These findings indicated that schizophrenia is associated with the loss of brain connectivity.

Wang and colleagues[94]used the ALL template along with white matter fiber tracts data collected using DTI to map the brain into 90 areas, and analyzed the white matter fiber tracts network using fiber tracking technology and graph-theory-based complex network analysis. They found that the normal characteristics of the topography of the brain network changed in patients with schizophrenia, resulting in a significant decrease in global efficiency that was correlated with scores on the Positive and Negative Syndrome Scale (PANSS). They also found decreased regional efficiency of some hubs,including the joint frontal cortex, paralimbic system,limbic system, and left lentiform nucleus.

2.4.2 Functional brain network

Functional brain networks are constructed using time series data of functional brain activities. Brain networks are differentiated into brain networks based on regions of interest, brain networks with specific functions, and whole brain networks. Examples of brain networks based on regions of interest are the dorsal lateral prefrontal lobe network and the medial prefrontal lobe network. Examples of specific brain networks are the default mode network (DMN) and the fronto-parietal network (FPN).[91]

Zhou and colleagues[95]studied the functional connection of the bilateral dorsal lateral prefrontal cortex (DLPFC); they found that patients with schizophrenia had reduced functional connection between the DLPFC and the parietal lobe, post cingulate gyrus, thalamus and striatum, but increased functional connection between the left DLPFC and the left midanterior temporal lobe and paralimbic regions. Fan and colleagues[96]studied the functional connection of the vetromedial prefrontal cortex (vMPFC) in patients with schizophrenia; they found (a) decreased functional

connection between the vMPFC and the medial frontal lobe, right middle temporal gyrus, right hippocampus,parahippocampal gyrus and amygdale, (b) decreased strength of the negative correlation between the vMPFC and the bilateral DLPFC and anterior supplementary motor area, and (c) a positive correlation between the reduction in the vMPFC-DLPFC connection and the positive symptoms of schizophrenia.

Table 4. Diffusion tensor imaging (DTI)studies on schizophrenia in China

Tang and colleagues[97]studied the default mode network (DMN) in patients with early-onset schizophrenia (12 to 19 years old); they found increased functional connection between the ventromedial prefrontal lobe and the right inferior temporal gyrus,left angular gyrus, and dorsomedial prefrontal lobe,but decreased functional connection between the right angular gyrus and the cerebellar tonsil, left superior frontal gyrus and right inferior semilunar lobule. Chang and colleagues[98]studied the anterior and posterior DMN as well as the left lateral and right lateral frontopariental networks (FPN); they found (a) abnormal intranetwork connections in the anterior DMN and bilateral FPN in both patients with schizophrenia and their healthy siblings, (b) normal intra-network connection of the posterior DMN, (c) a positive association between the two networks in patients with schizophrenia, their healthy siblings, and healthy controls, and (d) a stronger functional connection between the right FPN and the anterior DMN in patients with schizophrenia than in healthy controls.

Other researchers studied schizophrenia from the perspective of inherent networks, and proposed that the inherent networks include a task-positive network(TPN) and a task-negative network (TNN). Kong and colleagues[99]found increased functional connection in the bilateral inferior temporal gyrus of the TNN among individuals with schizophrenia and their healthy siblings;they also found increased functional connection between the left DLPFC and the right inferior temporal gyrus of the TPN among individuals with schizophrenia.Zhou and colleagues[100]assessed the TNN and TPN in patients with paranoid schizophrenia and found abnormal TNN functional connections with the bilateral dorsomedial prefrontal cortex, lateral parietal lobe, and inferior temporal gyrus, and abnormal TPN functional connections with the DLPFC and the right dorsal premotor cortex.

Liang and colleagues[101]used the ALL template to divide the brain into 116 areas, and analyzed the whole brain network using a complex network analysis method based on graph theory. They found that the functional brain connection of patients with schizophrenia during the resting state showed a wide-spread decline. Ke and colleagues[102]compared the properties of the brain network of patients with schizophrenia who primarily have positive symptoms with that of patients who primarily have negative symptoms; they found that the decline in the ‘small-world’ network was more pronounced in the patients with negative symptoms.

Guo and colleagues[103]assessed first order symmetry(the strength of the functional connection between the same brain regions from opposite hemispheres) and second order symmetry (the functional connection between the same pairs of brain regions from opposite hemispheres). They found that patients with schizophrenia had significantly decreased first and second order symmetry: the decrease in the first order symmetry indicated a reduced synchronicity between the two hemispheres; the decrease in the second order symmetry indicated a pronounced difference between the functional networks in the two hemispheres. They then compared the brain areas that were connected by the corpus callosum (CC) and the anterior commissure(AC) in patients with schizophrenia, and found that first and second order symmetry decreased in brain areas connected by the CC, but only first order symmetry decreased in brain areas connected by AC.

Liu and colleagues[104]assessed the diagnostic distinctiveness of the resting-state whole brain network.They found an 80.4% accuracy in distinguishing patients with schizophrenia from healthy controls, a 77.6%accuracy in distinguishing patients with schizophrenia from their healthy siblings, and a 78.7% accuracy in distinguishing schizophrenia patients’ healthy siblings and healthy controls without relatives with schizophrenia. These results suggest that the restingstate brain network of the patients’ siblings without schizophrenia is also changed in ways that distinguish it both from the brain network of their ill siblings and from that of healthy controls without a family history of mental illness.

3. Conclusions and future directions

In the past 30 years, advances in imaging technology and data analysis techniques have transformed neuroimaging into an exciting field that is rapidly advancing our understanding of the normal and abnormal functioning of the brain. These methods have identified structural and functional abnormalities in the brains of individuals with schizophrenia that confirm the biological basis of the disorder. However, much more multi-disciplinary work will be needed to integrate these findings into a comprehensive model of the etiology of this complex disorder. Chinese investigators have been and will continue to be enthusiastic participants in this global effort to understand, treat, and, hopefully,prevent this devastating condition.

Future neuroimaging research needs to overcome several central problems.

(a) Schizophrenia is highly heterogeneous, so dividing individuals with the clinical diagnosis into relatively homogeneous subgroups is essential to identifying distinct biological markers using neuroimaging techniques. The traditional methods of categorizing subtypes (paranoid,adolescent-onset, catatonic, simple, etc.) are obviously insufficient for research purposes. The dimensional approach based on rating the severity of 8 core symptoms of psychosis suggested in DSM-5[105]may be an improvement, but the utility of this method has not yet been assessed.

(b) There are some basic limitations to neuro-imaging that need to be overcome. Re-construction of images of white matter fiber tracts using DTI still has many methodological problems, including the false connections that can appear when reconstructing crossing fibers or longer fibers.[88]At present neuroimaging can only use MRI morphological data based on the population to construct a collective brain structural network; it cannot use data from a single participant to build an individualized brain structural network.

(c) Current brain network research is focused on the macro-level (whole brain or brain region)and relies on brain atlases (e.g., dividing the brain into 90 regions/nodes). Micro-level brain network research (neuron-level or voxellevel) may be more helpful for revealing the pathological mechanisms of a disorder, but such voxel-level studies will require much longer image processing time and more complex image analysis techniques.[87,88]Moreover, present brain network research describes associationsnotcause and effect relationships, so we do not know how the related brain areas work together to function effectively. Future research must construct directional networks that specify the directionality of the fiber connection between different brain regions and the causal relationship between neural activities.[87,88]

(d) More research in multi-modal imaging is needed to explore the potential benefits of combining methods. Many possible combinations are possible: structural MRI and resting-state fMRI;[106]resting-state fMRI and DTI;[107]neural imaging techniques based on MRI and EEG or MEG;[88]task-state fMRI and event-related potentials (ERP) or resting-state fMRI; and so forth. These multi-modal imaging methods can attain better results than single-mode methods by combining the complementary strengths of the different methods. For example, MRI has higher spatial resolution and EEG has better time resolution so combining the two methods provides a more multi-dimensional assessment.

(e) A parallel effort needs to be made in combining neuroimaging with genetics research[108,109]and with cognitive-behavioral research. Such a multi-disciplinary approach could reduce the necessary sample size of genetics research, help identify the genetic basis of the abnormal structure and function of the brain in schizophrenia, and clarify the link between altered genes, dysfunctional brains, and abnormal behavior.

Conflict of interest

The authors declare no conflict of interest related to this manuscript.

Funding

This review was funded by the National Science Foundation of China (81371479).

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2014-08-07; accepted: 2014-08-20)

Dr. Dengtang Liu graduated from Wuhan University School of Medicine in 1996 with a bachelor’s degree and obtained a doctoral degree in medicine from Fudan University School of Medicine in 2003. He has been working at the Shanghai Mental Health Center affiliated with Shanghai Jiao Tong University School of Medicine since 2003 and is a chief psychiatrist. He conducts both basic science and clinic research on mental illnesses with a primary focus on cognitive functioning, neuroimaging and clinical intervention studies of schizophrenia.

中國精神分裂癥的神經(jīng)影像學(xué)研究進(jìn)展

劉登堂, 徐一峰, 江開達(dá)

精神分裂癥，磁共振成像，磁共振波譜，彌散張量成像，中國

Summary:Since Hounsfield’s first report about X-ray computed tomography (CT) in 1972, there has been substantial progress in the application of neuroimaging techniques to study the structure, function, and biochemistry of the brain. This review provides a summary of recent research in structural and functional neuroimaging of schizophrenia in China and four tables describing all of the relevant studies from mainland China. The first research report using neuroimaging techniques in China dates back to 1983, a study that reported encephalatrophy in 30% of individuals with schizophrenia. Functional neuroimaging research in China emerged in the 1990s and has undergone rapid development since. Recently, structural and functional brain networks has become a hot topic among China’s neuroimaging researchers.

[Shanghai Arch Psychiatry. 2014; 26(4): 181-193.

http://dx.doi.org/10.3969/j.issn.1002-0829.2014.04.002]

Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China*correspondence: erliu110@126.com

A full-text Chinese translation of this article will be available at www.saponline.org on September 25, 2014.

概述：自Hounsfield于1972年首次報道X線計算機斷層掃描（CT）后，神經(jīng)影像學(xué)技術(shù)應(yīng)用持續(xù)發(fā)展，用于研究大腦結(jié)構(gòu)、功能和生物化學(xué)等方面。本文就中國近年來對精神分裂癥結(jié)構(gòu)性和功能性神經(jīng)影像學(xué)的研究做了一個概述并且用4個表格來描述中國大陸所有相關(guān)研究。國內(nèi)在精神科領(lǐng)域使用神經(jīng)影像學(xué)技術(shù)的首個研究報告可追溯至1983年，研究發(fā)現(xiàn)30%精神分裂癥患者存在腦萎縮。上世紀(jì)90年代國內(nèi)逐漸出現(xiàn)功能神經(jīng)影像學(xué)研究，并且快速發(fā)展。近年來，腦結(jié)構(gòu)網(wǎng)絡(luò)和腦功能網(wǎng)絡(luò)研究已成為中國神經(jīng)影像學(xué)研究的一個熱門話題。

本文全文中文版從2014年9月25日起在www.saponline.org可供免費閱覽下載