Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism_Journal of Biomedical Engineering

Authors：

WANG Longlong ^1,2 ,  LI Shuangyan ^1,2 , LI Runze ^1,2 ,  XU Guizhi ^1,2

1. State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300130, P. R. China;
2. Key Laboratory of Bioelectromagnetics and Neuroengineering of Hebei Province, Hebei University of Technology, Tianjin 300130, P. R. China;

Corresponding author：

LI Shuangyan, Email: lishuangyan@hebut.edu.cn; XU Guizhi, Email: gzxu@hebut.edu.cn

Keywords：

40 Hz light flicker stimulation; Spatial working memory; Phase-amplitude coupling; Neural oscillations; Hippocampus-medial prefrontal cortex

DOI：

10.7507/1001-5515.202212013

Video：

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive impairment, with the predominant clinical diagnosis of spatial working memory (SWM) deficiency, which seriously affects the physical and mental health of patients. However, the current pharmacological therapies have unsatisfactory cure rates and other problems, so non-pharmacological physical therapies have gradually received widespread attention. Recently, a novel treatment using 40 Hz light flicker stimulation (40 Hz-LFS) to rescue the cognitive function of model animals with AD has made initial progress, but the neurophysiological mechanism remains unclear. Therefore, this paper will explore the potential neural mechanisms underlying the modulation of SWM by 40 Hz-LFS based on cross-frequency coupling (CFC). Ten adult Wistar rats were first subjected to acute LFS at frequencies of 20, 40, and 60 Hz. The entrainment effect of LFS with different frequency on neural oscillations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was analyzed. The results showed that acute 40 Hz-LFS was able to develop strong entrainment and significantly modulate the oscillation power of the low-frequency gamma (lγ) rhythms. The rats were then randomly divided into experimental and control groups of 5 rats each for a long-term 40 Hz-LFS (7 d). Their SWM function was assessed by a T-maze task, and the CFC changes in the HPC-mPFC circuit were analyzed by phase-amplitude coupling (PAC). The results showed that the behavioral performance of the experimental group was improved and the PAC of θ-lγ rhythm was enhanced, and the difference was statistically significant. The results of this paper suggested that the long-term 40 Hz-LFS effectively improved SWM function in rats, which may be attributed to its enhanced communication of different rhythmic oscillations in the relevant neural circuits. It is expected that the study in this paper will build a foundation for further research on the mechanism of 40 Hz-LFS to improve cognitive function and promote its clinical application in the future.

Citation： WANG Longlong, LI Shuangyan, LI Runze, XU Guizhi. Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism. Journal of Biomedical Engineering, 2023, 40(6): 1142-1151. doi: 10.7507/1001-5515.202212013 Copy

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1. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer's disease: causes and treatment. Molecules. 2020, 25(24): 5789.
2. Wu L, Xian X, Xu G, et al. Toll-like receptor 4: A promising therapeutic target for Alzheimer's disease. Mediators Inflamm, 2022, 2022: 7924199.
3. Malaiya A, Singhai M, Singh M, et al. Recent update on the Alzheimer's disease progression, diagnosis and treatment approaches. Curr Drug Targets, 2022, 23(10): 978-1001.
4. Iaccarino H F, Singer A C, Martorell A J, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature, 2016, 540(7632): 230-235.
5. Singer A C, Martorell A J, Douglas J M, et al. Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc, 2018, 13(8): 1850-1868.
6. Chen M, Chen Y, Huo Q, et al. Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models. Mol Neurodegener. 2021, 16(1): 14.
7. Gaubert S, Raimondo F, Houot M, et al. EEG evidence of compensatory mechanisms in preclinical Alzheimer's disease. Brain. 2019, 142(7): 2096-2112.
8. 张雪, 袁佩君, 王莹, 等. 知觉相关的神经振荡-外界节律同步化现象. 生物化学与生物物理进展, 2016, 43(4): 308-315.
9. Adaikkan C, Tsai L H. Gamma entrainment: Impact on neurocircuits, glia, and therapeutic opportunities. Trends Neurosci, 2020, 43(1): 24-41.
10. Adaikkan C, Middleton S J, Marco A, et al. Gamma entrainment binds higher-order brain regions and offers neuroprotection. Neuron, 2019, 102(5): 929-943.
11. Martorell A J, Paulson A L, Suk H J, et al. Multi-sensory gamma stimulation ameliorates Alzheimer's-associated pathology and iImproves cognition. Cell, 2019, 177(2): 256-271.
12. Zheng L, Yu M, Lin R, et al. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun, 2020, 11(1): 3012.
13. Vivekananda U, Bush D, Bisby J A, et al. Theta power and theta-gamma coupling support long-term spatial memory retrieval. Hippocampus, 2021, 31(2): 213-220.
14. Mclaughlin A E, Diehl G W, Redish A D. Potential roles of the rodent medial prefrontal cortex in conflict resolution between multiple decision-making systems. Int Rev Neurobiol, 2021, 158: 249-281.
15. Zielinski M C, Shin J D, Jadhav S P. Coherent coding of spatial position mediated by theta oscillations in the hippocampus and prefrontal cortex. J Neurosci, 2019, 39(23): 4550-4565.
16. Labban S, Alshehri F S, Kurdi M, et al. Melatonin improves short-term spatial memory in a mouse model of Alzheimer's disease. Degener Neurol Neuromuscul Dis, 2021, 11: 15-27.
17. Victorino D B, Faber J, Pinheiro D J L L, et al. Toward the identification of neurophysiological biomarkers for Alzheimer’s disease in down syndrome: A potential role for cross-frequency phase-amplitude coupling analysis. Aging Dis, 2023,14(2): 428-449.
18. Tamura M, Spellman T J, Rosen A M, et al. Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. Nat Commun, 2017, 8(1): 2182.
19. Abubaker M, Al Qasem W, Kvašňák E. Working memory and cross-frequency coupling of neuronal oscillations. Front Psychol, 2021, 12: 756661.
20. Morici J F, Weisstaub N V, Zold C L. Hippocampal-medial prefrontal cortex network dynamics predict performance during retrieval in a context-guided object memory task. Proc Natl Acad Sci U S A, 2022, 119(20): e2203024119.
21. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals. 8th ed. Washington (DC): National Academies Press (US); 2011. DOI: 10.17226/12910.
22. Yang P, Wang Z, Zhang Z, et al. The extended application of the rat brain in stereotaxic coordinates in rats of various body weight. J Neurosci Methods, 2018, 307: 60-69.
23. Wang J, Zhang S, Liu T, et al. Directional prefrontal-thalamic information flow is selectively required during spatial working memory retrieval. Front Neurosci, 2022, 16: 1055986.
24. López-Madrona V J, Pérez-Montoyo E, Álvarez-Salvado E, et al. ferent theta frameworks coexist in the rat hippocampus and are coordinated during memory-guided and novelty tasks. Elife, 2020, 9: e57313.
25. Tort A B, Kramer M A, Thorn C, et al. Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task. Proc Natl Acad Sci U S A, 2008, 105(51): 20517-20522.
26. Tsoneva T, Garcia-Molina G, Desain P. Neural dynamics during repetitive visual stimulation. J Neural Eng, 2015, 12(6): 066017.
27. Lee K, Park Y, Suh S W, et al. Optimal flickering light stimulation for entraining gamma waves in the human brain. Sci Rep, 2021, 11(1): 16206.
28. He Q, Colon-Motas K M, Pybus A F, et al. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer’s disease. Alzheimers Dement (N Y), 2021, 7(1): e12178.
29. Zibrandtsen I C, Agger M, Kjaer T W. Gamma entrainment in a large retrospective cohort: Implications for photic stimulation therapy for Alzheimer's disease. J Alzheimers Dis, 2020, 75(4): 1181-1190.

Journal of Biomedical Engineering

Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism

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