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Clinical Trial
. 2024 Apr 11;15(1):3156.
doi: 10.1038/s41467-024-47263-y.

Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges

Lou T Blanpain  1   2   3 , Eric R Cole  1   3 , Emily Chen  1 , James K Park  1 , Michael Y Walelign  4 , Robert E Gross  1   5 , Brian T Cabaniss  6 , Jon T Willie  7 , Annabelle C Singer  8   9
Affiliations
Clinical Trial

Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges

Lou T Blanpain et al. Nat Commun. .

Abstract

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

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Conflict of interest statement

A.C.S. owns shares of and serves on the Scientific Advisory Board of Cognito Therapeutics. A.C.S. is an inventor on allowed U.S. Patent Application No. 16/979,226. Her conflicts are managed by Georgia Tech. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Auditory and visual flicker induce a steady-state evoked potential in human sensory regions.
A Intracranial local field potential (LFP) and single neuron activity were recorded while we exposed subjects to visual and auditory stimulation pulses. B In this first paradigm, we exposed subjects to 10 s trials of visual (V, orange), audio-visual (AV, green) or auditory (A, blue) flicker at 5.5 Hz, 40 Hz, 80 Hz and random non-periodic stimuli, as well as no stimulation or baseline (total of 13 conditions). C Example of 40 Hz-V steady-state evoked potential (EP) in early visual area lingual gyrus in one subject. Top: raw LFP trace at the beginning of a 40 Hz-V trial. Bottom left: post-operative computed tomography (CT) scan overlaid on pre-operative magnetic resonance imaging (MRI), with contact from which results are shown highlighted with white circle. Bottom middle: LFP response to 40 Hz-V flicker (orange) and baseline (black), averaged over 2 cycles of the stimulus. Bottom right: average power spectral density (PSD) plot of 40 Hz-V flicker versus baseline. For these last two plots, lines and shaded areas indicate mean +/− standard error of the mean (SEM). D Response to 40Hz-V stimulation across contacts (dots) located in early visual and auditory areas, on the Montreal Neurological Institute (MNI) normalized brain (top view), with color representing fold-change in power at the frequency of stimulation, capped at 10-fold increase to best visualize this range (n = 337 channels, 12 sessions, 12 subjects). Smaller gray dots indicate channels with no significant response. 34 contacts had modulation greater than 10-fold. The contact from which results are represented in (C) is highlighted with a gray circle. E Same as in (C) but illustrating 40 Hz-A steady-state EP in Heschl’s gyrus or transverse temporal gyrus (primary auditory area) from one subject during 40 Hz auditory stimulation (blue) or baseline (black). F Same as (D) but showing response to 40 Hz-A stimulation (n = 337 channels, 12 sessions, 12 subjects). One contact had modulation greater than the 10-fold threshold. The contact from which results are represented in (E) is highlighted with a gray circle. Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Audio-visual flicker induces a steady-state evoked potential in the human medial temporal lobe and prefrontal cortex.
A Example of 40 Hz-auditory (A) steady-state evoked potential (EP) in the hippocampus (HPC). (i) location of a depth electrode with contacts numbered from deep to superficial (zoomed-in below), in one subject, overlaid on pre-operative MRI; contacts 1–5 are in or near the hippocampus. (ii) Example local field potential (LFP) trace for the beginning of a 40Hz-A trial. (iii) For the same contact, averaged evoked potential over 2 cycles of the stimulus (left), averaged power spectral density (PSD) during 40Hz-A flicker (blue) and baseline (black, right). (iv) Averaged PSD for each contact from the depth electrode during 40Hz-A flicker, zoomed-in to show frequency of stimulation +/− 5 Hz (solid lines and shaded areas: mean +/− SEM), showing evoked responses in red contacts 3, 4, in the hippocampus, and weaker response in contacts 1, 6 and 7. B Same as (A), for a depth electrode in the superior prefrontal cortex (PFC) in a different subject, during 5.5 Hz-visual (V) flicker (orange). C Electrode contacts (dots) in the medial temporal lobe (MTL) and PFC that were modulated by 40 Hz-audiovisual (AV) flicker, on a MNI normalized brain (top view), with color representing fold-change in power at the frequency of stimulation, capped at 2-fold increase to best visualize this range (n = 793 contacts, 13 sessions, 13 subjects). Gray dots: contacts with no significant response. D Middle: fold-change in power (capped at 2-fold change) at 40 Hz during 40 Hz-AV flicker relative to baseline, for contacts with significant modulation; percent of electrodes showing significant steady-state EP above (n = 326 and 467 contacts, 13 sessions and subjects). Black open circles: medians, vertical lines: whisker plots, filled dots: each contact. 9 contacts had modulation higher than capped 2-fold change in the MTL, and 4 contacts in the PFC. Left and right: example power spectral densities during 40 Hz-AV flicker (green) or baseline (black) in the MTL and PFC, respectively. Lines and shaded areas: mean +/− SEM. Examples highlighted with red circles in the violin plots. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Flicker steady-state evoked potential across the brain.
A Top: Venn diagram showing proportion of contacts (n = 2067 contacts, 13 sessions, 13 subjects) with significant steady-state evoked potential (EP) to visual (V, orange), audio-visual (AV, green) and auditory (A, blue) flicker; absolute number of contacts are also shown. Center: Venn diagram showing significant responses to different flicker frequencies (5.5 Hz- light gray, 40 Hz- darker gray, 80 Hz- dark gray). Bottom: top stimulation frequency for each modality for contacts that responded to both visual and auditory flicker. Most contacts showed a preference for the same stimulation frequency when stimulated with either modality. B Approximate location of each contact (dots) and associated amplitude of steady-state EP, plotted on Montreal Neurological Institute (MNI) normalized brain (top view), for each of 9 conditions: 5.5 Hz, 40 Hz, 80 Hz stimulation frequencies at visual (V), audio-visual (AV) and auditory (A) modalities. Color of larger dots indicates power fold-change in channels with significant steady-state EP, from yellow to red (0–10-fold or more increase in power). Smaller gray dots indicate no significant response. C Distribution of 40Hz-AV flicker steady-state EP across all contacts showing significant modulation from all subjects, categorized by functional networks (as previously defined by resting state functional connectivity characterized across 1000 healthy subjects). Percent of contacts in that network with significant responses, with absolute number of contacts localized to those networks in parentheses (n = 1965 contacts, 13 sessions, 13 subjects). Open circles represent medians of the distributions, vertical lines indicate whisker plots, filled dots indicate each significant contact. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Flicker modulation does not result from linear superposition of single pulse evoked potentials.
A Schematic of the hypothesis that the steady state EP results from linear superposition of single pulse EPs: 40 Hz steady state EP (black) is hypothesized to result from the response to a single visual pulse (orange) that is repeated every 25 ms (transparent gray) and linearly summed. B 6 subjects were exposed to single 12.5 ms pulses in the visual (orange), audio-visual (green), and auditory (blue) modalities or relative occluded flicker (with sleep mask and earplugs) as control. C Percent of contacts showing response to flicker-only (red), single pulse-only (cyan), both flicker and single pulses (purple), and no response (gray), with the visual, audiovisual, and auditory modality, respectively. D Left: Example contacts that responded strongly to both (top) single visual pulses (left) and visual flicker (right) or more strongly to single pulses (bottom) during stimulation relative to control (black). Single-pulse EP (control is relative occluded audio-visual) and power spectral density (PSD) plots (control is baseline) shown for each. Lines and shaded areas: mean +/− SEM. Middle: Steady-state EP versus single-pulse EP amplitude, normalized by subject and stimulation modality; each dot represents one contact’s responses for a given modality; contacts with both significant steady-state EP and single-pulse EP were included (n = 319 contacts, 6 subjects). Red dots indicate examples on left. Right: Significance values of flicker versus single pulse response. E Left: Steady-state EP fold-change in power at 40 Hz in the visual, audio-visual, and auditory modalities, for real and simulated data across contacts (two-sided t-test; visual condition p = 0.0093, audio-visual condition p = 0.0081, auditory condition p = 2.5473 × 10−6; p-values are uncorrected for multiple comparisons and are lower than Bonferroni correction for 3 comparisons; n = 554 contacts, 6 subjects.) Only contacts showing significant flicker modulation in the real data were included. **p < 0.01, ***p < 0.001, open circles: medians, vertical lines: whisker plot, dots: each contact. Right: for those same contacts, amplitude of flicker steady-state EPs calculated using real data (x-axis) versus using simulated data (y-axis). Dots: one contact and modality. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Flicker response is dependent on intrinsic circuit properties.
A In the Flicker 5.5–80 Hz range paradigm, 8 subjects (11 sessions) were exposed to either visual (V, orange) or auditory (B, blue) modalities at 26 different frequencies spanning 5.5–80 Hz, random non-periodic flicker, and baseline (no stimulation). B Example contacts showing endogenous oscillations and response to stimulation frequencies. Top: power spectral density (PSD) during stimulation at each of 26 flicker frequencies, showing power values at the stimulation frequency +/− 1 Hz overlaid on the average baseline PSD (black) and aperiodic fit (1/f, gray). Lines and shading: mean +/− SEM. Bottom: fold-change in power (solid line) and phase-locking value (PLV, dotted line) for each stimulation condition. Vertical dashed colored line: stimulation frequency leading to maximal modulation, vertical dashed gray line: frequency of detected endogenous oscillation closest to top stimulation frequency, solid discs: significant fold-change, solid diamonds: significant PLV. C Normalized fold-change in power (left) at the frequency of stimulation and PLV (right), for each channel (rows) and frequency of stimulation (columns), normalized across stimulation frequencies. Some channels are repeated for subjects who underwent both the visual and auditory versions of the Flicker 5.5–80 Hz range paradigm (see Table S4). Channels with significant modulation to more than 6 stimulation frequencies shown above horizontal gray lines. Channels are ordered by top stimulation frequency from lowest to highest. Channels without significant modulation not shown. D Fold-change in power relative to aperiodic fit at the peak of each identified endogenous oscillation versus the frequency of that endogenous oscillation for all identified endogenous oscillations (see Methods) across all contacts (n = 904 contacts, 8 subjects, 11 sessions). Dot: 1 contact’s endogenous oscillation in a session. E Frequency of stimulation leading to maximal fold-change in power (top stimulation frequency) versus closest detected endogenous frequency, for all contacts (n = 184 contacts, 8 subjects, 11 sessions) that showed at least one endogenous oscillation at baseline and significant response to more than 6 of the flicker stimulation frequencies tested. Dot: one contact, dashed line: x = y, gray shaded area: +/−5 Hz from x = y. Source data are provided as a Source Data file.
Fig. 6
Fig. 6. Decrease of interictal epileptiform discharge rate in response to flicker.
A Example interictal epileptiform discharges (IEDs) detected (in red) over the first 3 s of a 40Hz-audiovisual (AV) trial, across 3 depth electrodes (labeled to the left as 20 Rd, 30 Rd and 32 Rd) that had channels which detected those IEDs. Each trace represents preprocessed local field potential (LFP) signal from a contact of the depth electrode labeled to the left. Flicker stimulus shown above. B Left: overall effect of any sensory flicker stimulation on the IED rate when including all channels (p = 2.4 × 10−5; 3094 channels, 19 subjects, 25 sessions). Middle: effect of sensory flicker on IED rate in channels that were non-modulated or weakly (<1.5 fold-change in power) modulated (non-mod/low-mod, versus baseline p = 2.8 × 10−4; 2936 channels) or strongly (>1.5 fold-change in power) modulated channels (high-mod, versus baseline p = 2.9 × 10−4; 158 channels; uncorrected p-values are lower than Bonferroni correction for 2 comparisons) by flicker stimulation (non-mod/low-mod versus high-mod p = 3.5 × 10−3). Right: change in IED rate by flicker stimulation modality (visual or V in orange, auditory or A in blue, and audiovisual or AV in green) and anatomical location of detected IEDs including visual- early visual regions, audio- early auditory regions, MTL- medial temporal lobe, PFC- prefrontal cortex (visual regions: visual flicker p = 2.6 × 10−6, 148 channels, 8 subjects, 9 sessions, audiovisual flicker p = 2.1 × 10−4, 24 channels, 2 subjects, 3 sessions; audio regions: audiovisual flicker p = 4.5 × 10−3, 162 channels, 7 subjects, 10 sessions; MTL: visual flicker p = 1.8 × 10−3, 472 channels, 17 subjects, 22 sessions, audiovisual flicker p = 1.6 × 10−8, 213 channels, 7 subjects, 10 sessions; PFC: audiovisual flicker p = 3.7 × 10−8, 261 channels, 6 subjects, 7 sessions; uncorrected p-values are lower than Bonferroni correction for 12 comparisons except increase in auditory regions during audiovisual flicker). For all plots, mean effect is represented by a dot, confidence interval of the effect is represented by a vertical bar; Poisson generalized linear mixed effects model for all statistical comparisons; *p < 0.05, **p < 0.01, ***p < 0.001. Source data are provided as a Source Data file.
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References

    1. Salanova V, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84:1017. doi: 10.1212/WNL.0000000000001334. - DOI - PMC - PubMed
    1. Bergey GK, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015;84:810. doi: 10.1212/WNL.0000000000001280. - DOI - PMC - PubMed
    1. Leoutsakos JMS, et al. Deep brain stimulation targeting the fornix for mild Alzheimer dementia (the ADvance trial): a two year follow-up including results of delayed activation. J. Alzheimers Dis. 2018;64:597–606. doi: 10.3233/JAD-180121. - DOI - PMC - PubMed
    1. Obleser J, Kayser C. Neural entrainment and attentional selection in the listening brain. Trends Cogn. Sci. 2019;23:913–926. doi: 10.1016/j.tics.2019.08.004. - DOI - PubMed
    1. Ward LM. Synchronous neural oscillations and cognitive processes. Trends Cogn. Sci. 2003;7:553–559. doi: 10.1016/j.tics.2003.10.012. - DOI - PubMed

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