Early life stress affects limited regional brain activity in depression

Early life stress (ELS) refers to an array of adversities occurring before sexual maturation, including physical, sexual, and emotional abuse, physical and emotional neglect, malnourishment, and loss of a parent1,2. ELS is highly prevalent and its incidence is higher in psychiatric populations3. It is also a risk factor for the development of various disorders such as major depressive disorder (MDD)4,5. ELS has been suggested to alter brain structure, including the prefrontal cortex, anterior cingulate cortex (ACC), hippocampus, amygdala, corpus callosum, and cerebellum6, as well as ACC-amygdala resting-state functional connectivity7 and default mode network (DMN) connectivity8. Previous task-based functional magnetic resonance imaging (fMRI) and resting-state blood flow studies have detected abnormal activation of the right hemisphere, cerebellum, basal ganglia, and medial temporal lobe in abused subjects9,10,11,12. Some studies focused on effects of life stress on brain in MDD, found early or recent stress may contribute to differences in fronto-limbic structures13, as well as prefrontal response to stimuli in MDD14,15. One fMRI study used a method based on whole brain and found that regional homogeneity decreased in the inferior parietal lobule and superior temporal gyrus in ELS subjects16, suggesting that ELS not only affects brain connectivity but also regional activity. The amplitude of low-frequency fluctuation (ALFF) is another parameter for analyzing resting-state fMRI data at the voxel level17. ALFF encodes physiologically meaningful indicators of blood oxygen level-dependent (BOLD) variation over time or dynamic fluctuations in intrinsic brain activity in the absence of explicit input, based on the fact that there are coherent low-frequency fluctuating BOLD signals in functionally related brain regions18,19. Fractional (f)ALFF is defined as the ratio of the power spectrum in the low frequency (0.01–0.08 Hz) range to that of the entire frequency range20, and may be regarded as a normalized version of ALFF. The ratio of ALFF/fALFF is a reliable and sensitive measure in the study of healthy21, epilepsy22, post-traumatic stress disorder (PTSD), and MDD23. Previous ELS-related neuroimaging studies have had various limitations. Firstly, most studies divided participants into those with or without ELS, which was determined based on the Childhood Trauma Questionnaire (CTQ); however, this excluded subjects that had experienced mild ELS8,16. Other studies did not provide a precise definition for ELS or used other questionnaires to establish ELS24. Secondly, many studies focused solely on healthy subjects, which did not enable an examination of the relationship between ELS and MDD12,25. In addition, most of the earlier studies investigating the effects of abuse used ROI approaches, which are biased towards fronto-limbic systems7 rather than taking into consideration the whole brain. Lastly, studies comparing ALFF/fALFF in MDD and healthy controls (HC) disregarded the fact that MDD patients typically score higher for ELS, which may contribute to the observed alterations. ELS can lead to aberrations in regional brain function that can heighten the risk of MDD in later life. However, not all MDD patients have a history of ELS, and some individuals exposed to ELS are resilient and healthy. It is therefore possible that ELS differentially affects MDD and healthy individuals. The present study investigated regional differences in brain function between MDD and HC as measured by ALFF/fALFF after regression of ELS, and examined the association of ELS with regional cerebral function in MDD and HC to determine differences in patterns of ELS-induced activity.