title: Altered neuronal spontaneous activity correlates with glutamate concentration in medial prefrontal cortex of major depressed females: An fMRI-MRS study.
abstract: Major depressive disorder (MDD) is twice more prevalent in females than in males. Yet, there have only been a few studies on the functional brain activity in female MDD patients and the detailed mechanisms underlying their neurobiology merit further investigations. In the present work, we used combined fMRI-MRS methods to investigate the altered intrinsic neuronal activity and its association with neurotransmitter concentration in female MDD patients.
  
  
  
  The whole brain amplitude of low frequency fluctuation (ALFF) analysis using resting state functional magnetic resonance imaging (fMRI) was performed to explore the alteration of intrinsic neuronal signals in MDD females (n=11) compared with female healthy controls (n=11). With a specific interest in the medial prefrontal cortex (mPFC) area, we quantified the concentration of amino acid neurotransmitters including GABA ((r-aminobutyric acid)), Glu (Glutamate), and Glx (Glutamate + Glutamine) using (1)H-MRS technology. Moreover, we conducted Pearson correlation analysis between the ALFF value and neurotransmitter concentration to find out the functional-biochemical relation in mPFC area. The relationship between the metabolites concentration and MDD symptomatology was also examined through Spearman correlation analysis.
  
  
  
  We found that the female MDD patients showed increased neuronal spontaneous activity in left medial prefrontal cortex (mPFC) and left middle frontal cortex, with decreased ALFF level in right putamen and right middle temporal cortex (p<0.01, Alphasim corrected). The ALFF in mPFC was shown positively correlated with Glu concentration in female MDD patients (r=0.67, p=0.023). The Glu concentration in mPFC was positively correlated with patients HAMA scores (r=0.641, p=0.033).
  
  
  
  The relatively small sample size, metabolite information acquired only in mPFC and not all patients were unmedicated are the major limitations of our study.
  
  
  
  Using combined fMRI-MRS methods, we found increased spontaneous neuronal activity was correlated with Glu concentration in mPFC of female MDD patients. Other regions including left middle frontal gyrus, right putamen and middle temporal gyrus also showed altered spontaneous neuronal activities. The abnormal intrinsic neuronal activities in fronto-cortical regions shed light on the pathogenesis underlying MDD females. The multimodal resting-state neuroimaging technique served as a useful tool for functional-biochemical investigation of MDD pathophysiology.
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xiaoliu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China; Department of EEG and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Departments of Pediatrics, Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston TX 77030, USA.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Maletic-Savatic
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China.
authors.forename: Xuanhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China; Department of EEG and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of EEG and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Shanbao
authors.initials: S
authors.lastname: Tong
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China; Department of EEG and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wanping Nan Road, Shanghai 200030, China. Electronic address: jijunwang27@163.com.
authors.forename: Jijun
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: yaoli118@gmail.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009474:Neurons / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: Female; Functional magnetic resonance imaging; Magnetic resonance spectroscopy; Major depressive disorder; Medial prefrontal cortex