An Gamma Oscillation Enhancement In Working Memory By Low-frequency RTMS

ObjectiveWorking memory(WM)is one of the important cognitive functions.Working memory dysfunction(WMD)is the main clinical manifestation of Alzheimer's disease(AD).It is of great significance to study effective tools to improve WMD in AD.Repeated transcranial magnetic stimulation(r TMS)is a noninvasive stimulating technique that can regulate neural activity in specific brain regions.Evidences show that high frequency r TMS can improve working memory function;however,whether low-frequency r TMS can improve working memory function still needs further study.In this study,local field potentials(LFPs)were recorded from rat prefrontal cortex during a working memory task.Effects of low frequency r TMS on working memory in control and WMD groups were analyzed from three respects,including behavior,gamma oscillation and network connection and the corresponding mechanism was investigated.This study is expected to provide theoretical and methodological support for the usage of low-frequency r TMS on the improvement of WMD in AD.Methods1.Animals and groups: 2.5-month-old male Sprague-Dawley(SD)rats were randomly divided into four groups: control group(Con),control with r TMS group(Con+r TMS),working memory dysfunction group(WMD),working memory dysfunction with r TMS group(WMD+r TMS).2.Preparation of rats with working memory dysfunction:5 ?l 36 h incubated A?1-42 was bilaterally injected into dentate gyrus(DG)area of dorsal hippocampus.Rats with working memory dysfunction were selected through a working memory task test on Y-maze.3.Application of low-frequency rTMS:Rats in the Con+r TMS and WMD+r TMS groups were treated by low-frequency(1 Hz)r TMS(400 stimuli daily)for 14 consecutive days.4.Working memory behavioral analysis:Correct percent and latency during the Y-maze working memory task were recorded and analyzed to investigate the characteristic patterns of behavioral performances.5.Acquisition of 16-channel LFPs from rat PFC during working memory:Implantable electrodes recording technique for awake animal was employed to record neural activity from rat PFC when the rats performed the Y-maze working memory task.The recorded neural activity was filtered(<500Hz)to obtain the 16-channel LFPs.LFPs were then preprocessed to remove baseline drift and power-line interference.6.Gamma oscillation based on time-frequency and coherence analysis:Short-time Fourier transform(STFT)was used to calculate power spectrum of LFPs during the working memory task.Coherence analysis was applied to estimate gamm oscillation.The characteristic patterns of gamma oscillation was assessed by energy density and spectral coherence.7.Functional connectivity in gamma network during working memory:Granger causality analysis was applied to estimate directed transfer function(DTF)among gamma-band LFPs during the working memory task,and functional connection characteristics in the gamma network were analyzed.Results 1.Y-maze working memory behavioral results:The performances of grouped rats were measured by correct percent.The correct percent in WMD,WMD+r TMS,Con and Con+r TMS group were 73.98±1.66%,83.13±2.98%,92.20±1.99% and 97.75±1.13%,respectively.The correct percent in the WMD group was significantly lower than that in the Con group.The correct percent in the Con+r TMS group was significantly higher than that in the Con group,and the correct percent in the WMD+r TMS group showed a significant increase,compared with that in the WMD group.2.Gamma oscillation: Time-frequency analysis results show that,the gamma power density increased and peaked at about 0.5s before the reference point in the Con group,and the averaged power density was 16.8257±0.5149?V2/Hz.While the gamma power density in the WMD group never experience such change,and the averaged power density(5.8569±0.4134?V2/Hz)was significantly lower than that in the Con group.The gamma power density in the Con+r TMS group and WMD+r TMS group experienced the similar changes as Con group.Averaged gamma power density in the Con+r TMS group(20.0425±0.4369?V2/Hz)was significantly higer than that in the Con group,and the gamma power density in the WMD+r TMS group(8.5434±0.4320?V2/Hz)showed a significant increase,compared with that in the WMD group.Gamma coherence in the Con group increased and peaked at about 0.5s before the reference point,and the averaged coherence was 0.5281±0.0183.While the gamma coherence in the WMD group never experience such change,and the averaged coherence(0.3217±0.0212)was significantly lower than that in the Con group.The gamma coherence in the Con+r TMS group and WMD+r TMS group experienced the similar changes as Con group.The averaged coherence in the Con+r TMS group(0.6018±0.0168)was significantly higer than that in the Con group,and the coherence in the WMD+r TMS group(0.4658±0.0179)showed a significant increase,compared with that in the WMD group.3.Functional connectivity of gamma network:Functional connectivity in the Con group increased and peaked at about 1.2s before the reference point,and the averaged DTF was 0.0905±0.0029.While the fuctional connectivity in the WMD group never experience such change,and the averaged DTF(0.0631±0.0040)was significantly lower than that in the Con group.The fuctional connectivity in the Con+r TMS group and WMD+r TMS group experienced the similar changes as Con group.The averaged DTF in the Con+r TMS group(0.1025±0.0032)was significantly higer than that in the Con group,and the DTF in the WMD+r TMS group(0.0832±0.0023)showed a significant increase,compared with that in the WMD group.Conclusions 1.A? accumulation in hippocampus led to WMD in rats.The accuracy of working memory behavioral of rats in the Y-maze is declined and gamma oscillation during working memory is absent,suggesting the brain network defects.2.Low frequency r TMS improved working memory function in the control group: working memory behavior were improved,gamma oscillation were enhanced,and functional connectivity of gamma network was enhanced.3.Low frequency r TMS improved working memory function in the WMD group: working memory behavior were improved,gamma oscillation were enhanced,and functional connectivity of gamma network was enhanced.