Neural activity changes in unaffected children of patients with schizophrenia: A resting-state fMRI study

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Abstract

Previous neuroimaging studies have suggested that individuals at risk for schizophrenia exhibit structural and functional brain abnormalities. However, few studies focus on resting state baseline activity in individuals with genetic high-risk for schizophrenia (HR). We examined cerebral spontaneous neural activity in HR by measuring the amplitude of low frequency fluctuations (ALFF) in the blood oxygen level-dependent (BOLD) functional magnetic resonance signal during resting state. Using a 3 T MRI scanner, 28 non-psychotic young adult participants with at least one parent with schizophrenia and 44 matched unrelated healthy comparison subjects (HC) were scanned during the resting-state. The ALFF of the BOLD signal for each participant was calculated, and these values were then compared between-groups using voxel-based analysis of the ALFF maps. The HR group showed significantly increased ALFF compared to the HC group in the striatum, including the left caudate nucleus extending to the putamen and the right caudate nucleus. There was also increased ALFF in HR relative to controls in the left medial temporal region including hippocampus, parahippocampal gyrus and the fusiform gyrus, as well as regions including the left lateral thalamus, bilateral ventral and dorsal anterior cingulate cortex, bilateral calcarine sulcus and precuneus. There was significantly decreased ALFF in the HR group relative to controls in the left inferior parietal lobule/postcentral gyrus. Our findings suggest that altered intrinsic neuronal activity in cortico-striato-thalamic networks may represent genetic vulnerability for the development of schizophrenia.

Introduction

Schizophrenia is considered a highly heritable familial disease. A growing body of evidence suggests that it is a neurodevelopmental disorder (Raedler et al., 1998) and that genetic factors play a strong role in its pathogenesis (Cannon, 2005, Cardno and Gottesman, 2000, Gottesman and Shields, 1966). However, the mechanism for genetic mediation of cerebral neurodevelopment in schizophrenia is still unclear. It is proposed that the pathophysiological processes of schizophrenia may be present prior to clinical symptom manifestation (Keshavan et al., 2005, Raedler et al., 1998, Weinberger, 1987). Therefore, it is important to study unaffected relatives during the peak ages for the development of schizophrenia. By examining genetically high-risk relatives of schizophrenia patients, particularly unaffected children of patients with schizophrenia, it may be possible to discover susceptibility factors for premorbid dysfunction before illness onset (Gottesman and Shields, 1973, Keshavan et al., 2004, Keshavan et al., 2005). Such research may provide insights into possible preventive measures or even interventions for this severe and debilitating illness.

Previous neuroimaging studies of unaffected family members of patients with schizophrenia have primarily employed structural or task-based fMRI methods. Structural MRI has shown that the children of schizophrenia patients display some cortical and subcortical brain abnormalities in regions such as the fronto-parietal lobes (Prasad et al., 2010), superior temporal gyrus (Rajarethinam et al., 2004), caudate (Rajarethinam et al., 2007), and the amygdala and hippocampus (Keshavan et al., 2002). Functional imaging studies, including positron emission tomography (PET) and task-based blood oxygenation level dependent (BOLD) functional MRI (t-fMRI) have also been used to explore brain activity alterations in relatives of schizophrenia patients. For example, using PET, Hirvonen et al. report increased caudate D2 receptor availability in unaffected co-twins of patients with schizophrenia (Hirvonen et al., 2005). Furthermore, a recent t-fMRI study of children of patients with schizophrenia suggests inefficient fronto-striatal responses during a working memory task (Diwadkar et al., 2012). Alterations in cortico-subcortical functioning may characterize schizophrenia diathesis and reflect vulnerability for the illness.

Few studies focus on resting-state fMRI (r-fMRI) in the offspring of schizophrenia subjects; however, the frequency of reported abnormalities of cortico-subcortical networks in HR subjects suggests that these alterations may play a vital role in the early stages of schizophrenia. Since Biswal et al. (1995) first reported the presence of spatially coherent activity in resting-state fMRI signal, increasing attention has focused on resting-state functional magnetic resonance imaging. Low-frequency fluctuations (LFFs; < 0.08 Hz) of the blood oxygen level-dependent (BOLD) signal are thought to be related to spontaneous neuronal activity during resting state and have been found to be highly synchronous in healthy subjects (Biswal et al., 1995, Cordes et al., 2000). Resting-state fMRI studies have already provided valuable insights into the pathophysiology of schizophrenia (Hoptman et al., 2010, Huang et al., 2010, Jafri et al., 2008, Yu et al., 2012, Zhou et al., 2007). It is unclear whether the children of schizophrenia patients demonstrate similar abnormalities of intrinsic or spontaneous brain activity patterns. In the present study, we used a recently developed approach termed amplitude of low-frequency fluctuation (ALFF), to measure resting-state local brain activity in HR.

ALFF has been used as a reliable and sensitive measurement in various mental disorders including schizophrenia (Hoptman et al., 2010, Huang et al., 2010, Yu et al., 2012). It is a measurement of regional spontaneous neuronal fluctuations in BOLD time course (Zang et al., 2007, Zuo et al., 2010). Previous studies suggest that ALFF is higher in grey matter than in white matter (Zuo et al., 2010), and that it can differentiate physiological brain states (Yan et al., 2009, Yang et al., 2007). Abnormal ALFF may reflect altered spontaneous neuronal activity and may help to locate impaired brain regions in resting-state. The ALFF method allows for measurement of spontaneous neuronal activity information that cannot be obtained from structural and task-based neuroimaging studies. In this study, we compared whole-brain ALFF between HR and unrelated healthy comparison subjects. We hypothesized that the offspring of schizophrenia would have altered resting-state ALFF.

Section snippets

Participants

Twenty-eight non-psychotic HR subjects (mean age 20.64 ± 5.02 years, 9 females/19 males) with at least one parent diagnosed with schizophrenia were recruited from the Department of Psychiatry, First Affiliated Hospital of China Medical University and Mental Health Center of Shenyang by advertisement. Parental diagnosis of schizophrenia was confirmed using DSM-IV criteria; all other Axis I diagnoses were ruled out. Forty-four unrelated healthy comparison participants (HC, mean age 20.55 ± 4.03 years,

Results

There were no significant differences between HR and HC groups in age (p = 0.93), gender (p = 0.46) or years of education (p = 0.34). The HR group showed significantly increased ALFF compared to the HC group in the striatum, including the left caudate nucleus extending to the putamen and the right caudate nucleus. There was also increased ALFF in HR relative to controls in the left medial temporal region including hippocampus, parahippocampal and fusiform gyrus. Additional regions included the left

Discussion

In the present study, we adopted a novel ALFF approach to estimate resting-state local brain activity in HR. We found that our HR group showed increased ALFF in several brain regions, including the striatum, medial temporal regions, the anterior cingulate and the calcarine/precuneus, as well as decreased ALFF in the left inferior parietal/postcentral gyrus, compared to the HC group. To the best of our knowledge, this is the first study to examine altered ALFF in the offspring of schizophrenia

Limitations

This study investigated the brain function of unaffected high familial risk children of schizophrenia patients. Studies of this population avoid confounding factors in affected individuals such as the effects of treatment and medications, chronicity of the illness, and the effects of compensatory neural responses. However, some limitations need to be addressed. Our current study is of modest size and future studies will recruit more participants to examine the neurobiological model we describe

Conclusion

In summary, we observed significant alterations in ALFF at resting state in a cortico-striatal-thalamic network that includes increased ALFF in the striatum, ventral and dorsal anterior cingulate cortex, the medial temporal lobe and the calcarine regions as well as decreased ALFF in inferior parietal lobe in our genetically high risk sample of young adults. Our findings suggest that abnormal intrinsic neuronal activity in cortico-striato-thalamic networks may be associated with a predisposition

Role of funding source

The authors were supported by research grants from the National Natural Science Foundation of China (81071099,81271499, Yanqing Tang and 81101012, Feng Wu), Liaoning Education Foundation (Pandeng Scholar, Fei Wang), the Liaoning Science and Technology Foundation (2008225010, Yanqing Tang and 2011225018, Fei Wang), the Liaoning Doctor Scientific Foundation (20111099, Feng Wu), National Institute of Health (K01MH086621, Fei Wang), the National Alliance for Research on Schizophrenia and Depression

Contributors

Drs. Tang, Kaiyuan Chen, Xu and Fei Wang designed the study. Drs. Zhou, Ye Wang, Xiaofan Chen, Jiang, Kong, Li, Wu, Zhe Wang acquired data. Drs. Kaiyuan Chen, Liu, Driesen and Edimiston analyzed data. Drs. Tang, Kaiyuan Chen, Liu, Driesen, Edmiston, Xu and Fei Wang wrote the article. All authors reviewed the article and provided approval for publication.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

We thank all participants and their families for their invaluable cooperation.

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