Electrophysiological differences between high and low frequency rTMS protocols in depression treatment.

Repetitive transcranial magnetic stimulation (rTMS) is a rapidly expanding mean in drug resistant depression treatment. Yet, despite vast research in this field, exact neurophysiological mechanism of rTMS therapy still remains unclear. This results in difficulties choosing suitable rTMS parameters in advance and compromises thorough evaluation of efficacy after the treatment. In order to obtain more explicit assessment of rTMS therapy in the psychiatric field, we evaluated and compared the influence of two most widely used antidepressive rTMS protocols on EEG band power spectrum and relation to clinical test scores (MADRS, BDI, HAM-D17). Forty-five patients (12 male, 33 female, mean age 52.16 years) participated in the study. Twenty-three patients received high frequency (10 Hz) stimulation, the rest 22 were stimulated using low frequency (1 Hz) protocol. Both groups received 10 to 15 daily rTMS sessions. EEG recordings and clinical tests were obtained the day before rTMS course and same day after the last session. Majority (57.78%) of patients showed considerable improvement after the treatment. There were no notable differences in clinical test score drop between the two rTMS protocols. However, we found that different protocols resulted in significantly different electrophysiological changes. High frequency (10 Hz) rTMS resulted in widespread changes off EEG band power, including delta power increase on the left hemisphere and alpha power growth on the right. Theta power increase was also obtained in parietal-occipital areas. Low frequency (1 Hz) rTMS showed to have no major effect on basic EEG band power, however, we found a notable shift of frontal alpha power asymmetry towards the right hemisphere, which correlated with the clinical outcome. Our study results suggest that two widely used rTMS protocols strongly differ in their electrophysiological mechanisms. Low frequency stimulation finesse on frontal alpha power asymmetry shift, whereas high frequency protocol acts on wider electrophysiological changes in the brain.

C/EBPα and PU.1 are involved in distinct differentiation responses of acute promyelocytic leukemia HL-60 and NB4 cells via chromatin remodeling.

C/EBPα and PU.1 are the basic transcription factors that control differentiation-related genes, including granulocyte- colony-stimulating factor (G-CSFR) and human neutrophil elastase (HNE). Here, we analyzed a role of C/EBPα and PU.1 in human acute leukemia cell lines, HL-60 and NB4, in association with a modified chromatin structure by histone deacetylase inhibitors, FK228, sodium phenyl butyrate and vitamin B3. We found that sodium phenyl butyrate alone and 6h-pretreatment with phenyl butyrate or FK228 before the induction of differentiation with all-trans-retinoic acid in the presence of vitamin B3 effectively accelerated and enhanced differentiation to granulocytes in HL-60 but not in NB4 cells as detected by NBT test and the expression of CD11b and CD114 (G-CSFR) using flow cytometric analysis. HDACIs induced a time- and dose-dependent accumulation of hyper-acetylated histone H4 in both cell lines with the delay in NB4 cells. Time-dependent different induction of HL-60 and NB4 cell differentiation was paralleled by the activation of C/EBPα and PU.1 binding to the G-CSFR and the HNE promoters in electrophoretic mobility shift assay. Chromatin immunoprecipitation analysis revealed histone H4 acetylation in the G-CSF receptor promoter at the C/EBPα binding site in HL-60 but not in NB4 cells under the combined treatment. The results indicate that epigenetic events, such as histone acetylation, are involved in the activity modulation of the key transcription factors responsible for the induction of granulocytic differentiation in promyelocytic leukemia cells.