Disturbances in primary visual processing as a function of healthy aging.

For decades, visual entrainment paradigms have been widely used to investigate basic visual processing in healthy individuals and those with neurological disorders. While healthy aging is known to be associated with alterations in visual processing, whether this extends to visual entrainment responses and the precise cortical regions involved is not fully understood. Such knowledge is imperative given the recent surge in interest surrounding the use of flicker stimulation and entrainment in the context of identifying and treating Alzheimer's disease (AD). In the current study, we examined visual entrainment in eighty healthy aging adults using magnetoencephalography (MEG) and a 15 Hz entrainment paradigm, while controlling for age-related cortical thinning. MEG data were imaged using a time-frequency resolved beamformer and peak voxel time series were extracted to quantify the oscillatory dynamics underlying the processing of the visual flicker stimuli. We found that, as age increased, the mean amplitude of entrainment responses decreased and the latency of these responses increased. However, there was no effect of age on the trial-to-trial consistency in phase (i.e., inter-trial phase locking) nor amplitude (i.e., coefficient of variation) of these visual responses. Importantly, we discovered that the relationship between age and response amplitude was fully mediated by the latency of visual processing. These results indicate that aging is associated with robust changes in the latency and amplitude of visual entrainment responses within regions surrounding the calcarine fissure, which should be considered in studies examining neurological disorders such as AD and other conditions associated with increased age.

Targeted rhythmic visual stimulation at individual participants' intrinsic alpha frequency causes selective increase of occipitoparietal BOLD-fMRI and EEG functional connectivity.

Neural oscillations in distinct frequency bands are ubiquitous in the brain and play a role in many cognitive processes. The "communication by coherence" hypothesis, poses that the synchronization through phase coupling of frequency-specific neural oscillations regulate information flow across distribute brain regions. Specifically, the posterior alpha frequency band (7-12 Hz) is thought to gate bottom-up visual information flow by inhibition during visual processing. Evidence shows that increased alpha phase coherency positively correlates with functional connectivity in resting state connectivity networks, supporting alpha mediates neural communication through coherency. However, these findings have mainly been derived from spontaneous changes in the ongoing alpha rhythm. In this study, we experimentally modulate the alpha rhythm by targeting individuals' intrinsic alpha frequency with sustained rhythmic light to investigate alpha-mediated synchronous cortical activity in both EEG and fMRI. We hypothesize increased alpha coherency and fMRI connectivity should arise from modulation of the intrinsic alpha frequency (IAF) as opposed to control frequencies in the alpha range. Sustained rhythmic and arrhythmic stimulation at the IAF and at neighboring frequencies within the alpha band range (7-12 Hz) was implemented and assessed in a separate EEG and fMRI study. We observed increased cortical alpha phase coherency in the visual cortex during rhythmic stimulation at the IAF as in comparison to rhythmic stimulation of control frequencies. In the fMRI, we found increased functional connectivity for stimulation at the IAF in visual and parietal areas as compared to other rhythmic control frequencies by correlating time courses from a set of regions of interest for the different stimulation conditions and applying network-based statistics. This suggests that rhythmic stimulation at the IAF frequency induces a higher degree of synchronicity of neural activity across the occipital and parietal cortex, which supports the role of the alpha oscillation in gating information flow during visual processing.

Visual light flicker stimulation: enhancing alertness in sleep-deprived rats.

Introduction: In the evolving field of neurophysiological research, visual light flicker stimulation is recognized as a promising non-invasive intervention for cognitive enhancement, particularly in sleep-deprived conditions. Methods: This study explored the effects of specific flicker frequencies (40 Hz and 20-30 Hz random flicker) on alertness recovery in sleep-deprived rats. We employed a multidisciplinary approach that included behavioral assessments with the Y-maze, in vivo electrophysiological recordings, and molecular analyses such as c-FOS immunohistochemistry and hormone level measurements. Results: Both 40 Hz and 20-30 Hz flicker significantly enhanced behavioral performance in the Y-maze test, suggesting an improvement in alertness. Neurophysiological data indicated activation of neural circuits in key brain areas like the thalamus and hippocampus. Additionally, flicker exposure normalized cortisol and serotonin levels, essential for stress response and mood regulation. Notably, increased c-FOS expression in brain regions related to alertness and cognitive functions suggested heightened neural activity. Discussion: These findings underscore the potential of light flicker stimulation not only to mitigate the effects of sleep deprivation but also to enhance cognitive functions. The results pave the way for future translational research into light-based therapies in human subjects, with possible implications for occupational health and cognitive ergonomics.

Rationale and design of a double-blinded, randomized placebo-controlled trial of 40 Hz light neurostimulation therapy for depression (FELIX).

BACKGROUND: Major depressive disorder (MDD) is a debilitating condition that affects more than 300 million people worldwide. Current treatments are based on a trial-and-error approach, and reliable biomarkers are needed for more informed and personalized treatment solutions. One of the potential biomarkers, gamma-frequency (30-80 Hz) brainwaves, are hypothesized to originate from the excitatory-inhibitory interaction between the pyramidal cells and interneurons. The imbalance between this interaction is described as a crucial pathological mechanism in neuropsychiatric conditions, including MDD, and the modulation of this pathological interaction has been investigated as a potential target. Previous studies attempted to induce gamma activity in the brain using rhythmic light and sound stimuli (GENUS - Gamma Entrainment Using Sensory stimuli) that resulted in neuroprotective effects in Alzheimer's disease (AD) patients and animal models. Here, we investigate the antidepressant, cognitive, and electrophysiological effects of the novel light therapy approach using 40 Hz masked flickering light for patients diagnosed with MDD. METHODS AND DESIGN: Sixty patients with a current diagnosis of a major depressive episode will be enrolled in a randomized, double-blinded, placebo-controlled trial. The active treatment group will receive 40 Hz masked flickering light stimulation while the control group will receive continuous light matched in color temperature and brightness. Patients in both groups will get daily light treatment in their own homes and will attend four follow-up visits to assess the symptoms of depression, including depression severity measured by Hamilton Depression Rating Scale (HAM-D17), cognitive function, quality of life and sleep, and electroencephalographic changes. The primary endpoint is the mean change from baseline to week 6 in depression severity (HAM-D6 subscale) between the groups.

Temporal correspondence in perceptual organization: Reciprocal interactions between temporal sensitivity and figure-ground segregation.

How do visual representations account for time? Is it the case that they represent time by themselves possessing temporal properties (temporal mirroring) or by atemporal markers/tags (temporal tagging)? This question has been asked for the past 5 decades and more, in neuroscience, philosophy, and psychology. To address this debate, we designed a study to test temporal correspondence. We tested whether a temporal property (flicker frequency) could influence figure-ground segregation, and in turn, reciprocally, whether a figure-ground segregation would alter a temporal property (here, temporal resolution). We manipulated flicker frequency of dots on either side of an ambiguous edge in Experiment 1 and asked participants to indicate the figural region. In Experiment 2, we measured temporal sensitivity using a temporal order judgment (TOJ) task in both figural and ground regions. We showed temporal correspondence by showing specifically that figure-ground segregation depends on flicker frequency differences between two regions in ambiguous displays, where slow-flickering regions are seen as figural (Experiment 1). Reciprocally, in Experiment 2, we showed that participants performed a temporal-order judgment task better when the task had to be performed on a region seen as background compared with the same region seen as a figure. We show how relatively slower flickering regions are seen as figural, and correspondingly, seeing a region as figural is associated with a poorer temporal resolution. Our results collectively allow us to demonstrate a tight temporal correspondence in figure-ground perception, which could be explained using the parvocellular and magnocellular pathways, the two major retino-geniculo-cortical pathways.

Cell-type-specific propagation of visual flicker.

Rhythmic flicker stimulation has gained interest as a treatment for neurodegenerative diseases and as a method for frequency tagging neural activity. Yet, little is known about the way in which flicker-induced synchronization propagates across cortical levels and impacts different cell types. Here, we use Neuropixels to record from the lateral geniculate nucleus (LGN), the primary visual cortex (V1), and CA1 in mice while presenting visual flicker stimuli. LGN neurons show strong phase locking up to 40 Hz, whereas phase locking is substantially weaker in V1 and is absent in CA1. Laminar analyses reveal an attenuation of phase locking at 40 Hz for each processing stage. Gamma-rhythmic flicker predominantly entrains fast-spiking interneurons. Optotagging experiments show that these neurons correspond to either parvalbumin (PV+) or narrow-waveform somatostatin (Sst+) neurons. A computational model can explain the observed differences based on the neurons' capacitative low-pass filtering properties. In summary, the propagation of synchronized activity and its effect on distinct cell types strongly depend on its frequency.

The Ganzflicker experience: High probability of seeing vivid and complex pseudo-hallucinations with imagery but not aphantasia.

There are considerable individual differences in visual mental imagery ability across the general population, including a "blind mind's eye", or aphantasia. Recent studies have shown that imagery is linked to differences in perception in the healthy population, and clinical work has found a connection between imagery and hallucinatory experiences in neurological disorders. However, whether imagery ability is associated with anomalous perception-including hallucinations-in the general population remains unclear. In the current study, we explored the relationship between imagery ability and the anomalous perception of pseudo-hallucinations (PH) using rhythmic flicker stimulation ("Ganzflicker"). Specifically, we investigated whether the ability to generate voluntary imagery is associated with susceptibility to flicker-induced PH. We additionally explored individual differences in observed features of PH. We recruited a sample of people with aphantasia (aphants) and imagery (imagers) to view a constant red-and-black flicker for approximately 10 min. We found that imagers were more susceptible to PH, and saw more complex and vivid PH, compared to aphants. This study provides the first evidence that the ability to generate visual imagery increases the likelihood of experiencing complex and vivid anomalous percepts.

Impact of Temporal Visual Flicker on Spatial Contrast Sensitivity in Myopia.

PURPOSE: To investigate whether short-term exposure to high temporal frequency full-field flicker has an impact on spatial visual acuity in individuals with varying degrees of myopia. METHODS: Thirty subjects (evenly divided between control and experimental groups) underwent a 5-min exposure to full-field flicker. The flicker rate was lower than critical flicker frequency (CFF) for the experimental group (12.5 Hz) and significantly higher than CFF for the controls (60 Hz). Spatial contrast sensitivity function (CSF) was measured before and immediately after flicker exposure. We examined whether the post flicker CSF parameters were different from the pre-exposure CSF values in either of the subject groups. Additionally, we examined the relationship between the amount of CSF change from pre to post timepoints and the degree of subjects' myopia. The CSF parameters included peak frequency, peak sensitivity, bandwidth, truncation, and area under log CSF (AULCSF). RESULTS: There was no significant difference of all five pre-exposure CSF parameters between the two groups at baseline (P = 0.333 ∼ 0.424). Experimental group subjects exhibited significant (P < 0.005) increases in peak sensitivity and AULCSF, when comparing post-exposure results to pre-exposure ones. Controls showed no such enhancements. Furthermore, the extent of these changes in the experimental group was correlated significantly with the participants' refractive error (P = 0.005 and 0.018, respectively). CONCLUSION: Our data suggest that exposure to perceivable high-frequency flicker (but, not to supra-CFF frequencies) enhances important aspects of spatial contrast sensitivity, and these enhancements are correlated to the degree of myopia. This finding has implications for potential interventions for cases of modest myopia.

Phase-specific manipulation of rhythmic brain activity by transcranial alternating current stimulation.

BACKGROUND: Oscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, modulation of neural activity by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the phase-specificity of tACS effects in humans is still critically debated. OBJECTIVE: Here, we investigated the phase-specificity of tACS on visually evoked steady state responses (SSRs) in 24 healthy human participants. METHODS: We used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS. A neural network model served to validate the plausibility of experimental findings. RESULTS: We observed a modulation of SSR amplitudes dependent on the phase shift between flicker and tACS. The tACS effect size was negatively correlated with the strength of flicker-evoked activity. Supported by simulations, data suggest that strong network synchronization limits further neuromodulation by tACS. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with SSR phase delays in the tACS target region. CONCLUSIONS: Overall, our data provide electrophysiological evidence for phase-specific modulations of rhythmic brain activity by tACS in humans. As the optimal timing of tACS application was dependent on cortical SSR phase delays, our data suggest that tACS effects were not mediated by retinal co-stimulation. These findings highlight the potential of tACS for controlled, phase-specific modulations of neural activity.

Modification of Brain Oscillations via Rhythmic Light Stimulation Provides Evidence for Entrainment but Not for Superposition of Event-Related Responses.

The functional relevance of brain oscillations in the alpha frequency range (8-13 Hz) has been repeatedly investigated through the use of rhythmic visual stimulation. The underlying mechanism of the steady-state visual evoked potential (SSVEP) measured in EEG during rhythmic stimulation, however, is not known. There are two hypotheses on the origin of SSVEPs: entrainment of brain oscillations and superposition of event-related responses (ERPs). The entrainment but not the superposition hypothesis justifies rhythmic visual stimulation as a means to manipulate brain oscillations, because superposition assumes a linear summation of single responses, independent from ongoing brain oscillations. Here, we stimulated participants with a rhythmic flickering light of different frequencies and intensities. We measured entrainment by comparing the phase coupling of brain oscillations stimulated by rhythmic visual flicker with the oscillations induced by arrhythmic jittered stimulation, varying the time, stimulation frequency, and intensity conditions. In line with a theoretical concept of entrainment (the so called Arnold tongue), we found the phase coupling to be more pronounced with increasing stimulation intensity as well as at stimulation frequencies closer to each participant's intrinsic frequency. Only inside the Arnold tongue did the conditions significantly differ from the jittered stimulation. Furthermore, even in a single sequence of an SSVEP, we found non-linear features (intermittency of phase locking) that contradict the linear summation of single responses, as assumed by the superposition hypothesis. Our findings provide unequivocal evidence that visual rhythmic stimulation entrains brain oscillations, thus validating the approach of rhythmic stimulation as a manipulation of brain oscillations.