Sex-dependent Alterations In Resting-sate CBF, ALFF And Their Coupling Relationship In Schizophrenia

Background: Sex difference is an important characteristic of the human brain, and the sex difference in cerebral blood flow(CBF) has been repeatedly revealed in both healthy subjects and patients with schizophrenia. We aimed to investigate sex-dependent alterations in resting-state CBF, amplitude of low-frequency fluctuations(ALFF) and CBF-ALFF coupling in patients with schizophrenia.Subjects and Methods: A resting-state functional MRI and a three-dimensional pseudo-continuous arterial spin labeling imaging were performed using GE Discovery MR750 3.0T magnetic resonance scanner to obtain resting-state ALFF and CBF in 95 schizophrenia patients(51 males and 44 females) and 99 healthy controls(43 males and 56 females). After data preprocessing, in the SPM8 software, a two-way analysis of covariance(ANCOVA) controlling for age effect was used to estimate sex differences in ALFF or CBF in each diagnostic group and diagnostic group differences in ALFF or CBF in each sex group. Making mask using the brain regions exhibited significant diagnostic group differences in CBF and ALFF, then using the union of two masks for comparison between groups of CBF-ALFF coupling. The CBF-ALFF coupling was calculated using partial correlation analysis, and a z-test was used to compare the differences in CBF-ALFF coupling between schizophrenia and healthy control groups. We employed a significant threshold of p < 0.001 to control the false positive findings from multiple comparisons.Results:(1) Sex difference in CBF was less prominent in patient group, although both groups shared similar distribution of brain regions. However, the distributions of brain regions with sex differences in ALFF were completely different between the two groups.(2) Compared to healthy subjects, patients with schizophrenia exhibited significant increased CBF in temporal cortex and basal ganglia, and decreased CBF in the anterior midline regions, lateral prefrontal cortex and part of occipital regions.Schizophrenia patients had decreased ALFF in the posterior brain regions(occipital and parietal cortices) and increased ALFF in the anterior brain regions(deep nuclei, and frontal and temporal cortices). Although male and female subjects shared similar distributions of brain regions with significant diagnostic group differences in CBF and ALFF, females had larger spatial extent than males. Brain regions with diagnostic group differences in CBF and ALFF only partly overlapped.(3) No significant group differences were found in CBF-ALFF coupling between the patients and healthy subjects in males. Compared to healthy female subjects, female patients with schizophrenia exhibited significant increased CBF-ALFF coupling in the right hippocampus, the right thalamus and the left precuneus.Conclusion: Sex-specific changes in brain structural and functional characteristics are important features in schizophrenia, which should be considered in future neuroimaging studies. The CBF and ALFF have different sensitivity in detecting changes in neuronal activity in schizophrenia and can provide complementary information.