| Alertness refers to the ability of the human body to maintain rapid perception and response to information over a long period of time.Decreased alertness may lead to delayed reaction and information omission.Flashing stimulation can induce neural entrainment,improve brain cognitive function,and affect the physiological processes related to the circadian rhythm system,thereby enhancing alertness.However,the mechanism of neural entrainment induced by flashing stimulation is still unclear,and the effects and parameters of alertness enhancement need to be verified and optimized.These issues limit the application of flashing stimulation in alertness intervention.This article focuses on the research of the neural entrainment mechanism induced by flashing stimulation and its effects on alertness enhancement,mainly including the following three aspects:1.Mechanism of flash-induced neural entrainment based on neural network modelBased on anatomical experimental data,a neural network model of retina-thalamus-cortex was constructed based on the Hodgkin-Huxley model and adaptive exponential integrate-and-fire model.The action potential firing pattern of retinal ganglion cells under flash stimulation was based on the frequency,intensity,and duty cycle of flash stimulation.The thalamus-cortex network comprises six types of neurons: relay thalamic cell(RTC),high-threshold bursting thalamic cell(HTC),interneuron(IN),reticular inhibitory neuron(RE),pyramidal neuron(RS),and fast-spiking inhibitory neuron(FS).The interaction mechanism between flash stimulation at different frequencies(30-50 Hz,with a step of 1 Hz),intensities(low,medium,high),duty cycles(10%,30%,50%,70%,and 90%)and network neural oscillations was simulated in different oscillation states(mainly oscillations at α,β,or γfrequency).The results showed that the effect of flashing stimulation on the neural network was related to its own oscillation state.The 30-50 Hz flashing stimulation failed to induce neural entrainment entrainment under the α oscillation state,but accelerated the oscillation frequency of the network and inhibited the strength of the oscillation.The frequency band range close to the stimulation frequency under the β andγ oscillation states can induce neural entrainment.Under the 40 Hz flashing stimulation frequency,the flashing stimulation with a duty cycle ≤ 50% can induce neural entrainment more effectively than the flashing stimulation with a duty cycle >50%.For flashing stimulation with different frequencies and intensities,the frequency range of entrainment was not continuous,indicating the nonlinear system characteristics of the simulated network.2.Neural oscillation response characteristics induced by flash stimulation based on electrophysiological experimentsTaking rats as the research objects,the neural signal response characteristics of the lateral geniculate nucleus under flash stimulation of different parameters were collected and analyzed based on electrophysiological experiments,including local field potential(LFP)and action potential(AP).First,the LFP at 30 Hz,32 Hz,34 Hz,…,50 Hz were collected,and the frequency and time domain characteristics of the neural oscillation response were analyzed through LFP power spectrum and frequency spectrum heatmap calculation to verify the results of the simulation study.Second,a 20-30 Hz random flash stimulation pattern targeting high-frequency band neural oscillations(β and γfrequencies)associated with alertness was constructed to analyze the neural signal response characteristics of the lateral geniculate nucleus and create a flash stimulation program that can enhance high-frequency neural oscillations and inhibit low-frequency neural oscillations.Finally,a linear state space model was constructed to predict the power spectral density of neural oscillations in different frequency bands of LFP power spectrum under a 20-30 Hz random flash stimulation pattern,providing a technical basis for flash-based closed-loop neural regulation.The results indicated that single-frequency flashing stimulation could inhibit low-frequency neural oscillations,and the strength of the induced neural entrainment was related to the neural network’s own oscillation state.When the neural network had a higher oscillation intensity(in the frequency range of ≤40 Hz),the induced neural entrainment also had a higher intensity.Random flashing stimulation in the range of 20-30 Hz could induce enhanced neural oscillations in the corresponding frequency ranges of 20-30 Hz,40-60 Hz,and 60-90 Hz.Statistical results showed a significant decrease of PSD in the θ frequency band and a significant increase of PSD in the β and γ frequency bands,indicating that this flashing stimulation paradigm could enhance alertness.Under random flashing stimulation in the range of 20-30 Hz,the lateral geniculate neurons of the thalamus exhibited two response patterns: increased or decreased spike firing rates.The increase in spike firing rates was significant,indicating enhanced excitability of the neurons.The PSD of neural oscillations in the high-frequency range(60-90 Hz)under random flashing stimulation in the range of 20-30 Hz showed higher predictive accuracy,suggesting a higher feasibility of closed-loop neural regulation targeting the PSD of high-frequency neural oscillations.3.Alertness enhancement effect of flash stimulation in sleep-deprived ratA sleep deprivation model in rats was constructed.Firstly,the protein expression level of brain activation marker C-FOS under flash stimulations was detected through immunohistochemical analysis,and its effect on alertness was verified through open field and Y-maze behavioral experiments.Then,by taking blood samples from the inner corner of the rat’s eye and analyzing it through enzyme-linked immunosorbent assay and blood cell analysis,the effects of flash stimulations on cortisol,serotonin,and melatonin,as well as potential immunostress effects,were explored.Finally,hippocampal and hypothalamic tissues were harvested to investigate the possible effects of gene expression regulation on the enhanced alertness induced by flash stimulations,through transcriptomic analysis and quantitative polymerase chain reaction(q PCR)experiments.Immunohistochemistry results indicate that the flash stimulation activates secondary structures of the thalamus,including the suprachiasmatic nucleus(SCN),superior colliculus(SC),ventrolateral preoptic nucleus(VLPO),and lateral geniculate nucleus(LGN),suggesting the central role of the thalamus in modulating cognitive functions through flicker intervention.Open field and Y-maze behavioral experiments demonstrate that both types of flash stimulation significantly enhance exploratory behavior and activity in sleep-deprived rats,but show no significant difference in normal rats,indicating that both types of flash stimulation increase excitability in sleep-deprived rats.Sleep deprivation significantly increases serum concentrations of serotonin and cortisol in rats,while both types of flicker stimulation promote the recovery of serotonin and cortisol,thereby improving the mental state of sleep-deprived rats.Sleep deprivation induces immune stress responses in rats,characterized by a decrease in lymphocytes and an increase in neutrophils,and both types of flash stimulation can promote the recovery of this immune response.Additionally,transcriptomic sequencing results suggest that genes Cdh1,Gata2,Hes5,and Klf4 play important roles in the alertness-enhancing effects induced by flicker stimulation. |
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