Periodic Reporting for period 1 - ResonanceCircuits (Illuminating neural microcircuitry underlying flicker resonance in the visual cortex)
Período documentado: 2020-12-15 hasta 2022-12-14
Rhythmic sensory stimuli elicit oscillatory brain responses at the frequency identical or harmonically related to the stimulus. Aside from this frequency following response, increased amplitude (or resonance) responses are observed in response to ~10, ~20, and ~40 Hz in humans. Already one of the first studies using electroencephalography (EEG) in humans demonstrated that the amplitude of alpha brain rhythm (7-13 Hz) could be increased in amplitude when periodic light flashes were in synchrony with individual endogenous alpha rhythm (~10Hz; Adrian & Matthews, 1934). This study was the first to raise the possibility that light could noninvasively modulate brain rhythms. This posibility has been recently demonstrated (Iaccarino et al., 2016): Repetitive light therapy using 40 Hz visual stimulation has been shown to improve cognitive performance in Alzheimer disease mouse model by affecting synaptic transmission and synaptic plasticity, and as such, preserving neurons and synapses.
Rhythmic sensory stimulation (flicker) has many applications: From human vision and cognitive neuroscience research to visual impairment diagnostics. Aberrant responses to flicker stimulation have also been used as diagnostic tools in clinical neuroscience (e.g. schizophrenia, mood disorders, epilepsy, migraine). Why do responses to alpha flicker predict effectiveness of medication? Why can alpha flicker trigger epileptiform dynamics? Answers to these questions require understanding the neural mechanisms underlying responses to rhythmic stimulation.
Despite a long history and applications, the neural mechanisms by which rhythmic sensory stimuli interact with and modulate endogenous brain rhythms, are unknown. The objectives of this project were to: (1) measure the interactions between exogenous rhythms and endogenous brain oscillations at the level they are generated using high-density laminar probes that enable recording from hundreds of neurons across cortical laminae; (2) optogenetically identify and manipulate different classes of neurons. This fundamental research knowledge on interactions between exogenous and endogenous rhythms holds realistic promise in the clinical domain for diagnosis and therapeutic interventions of oscillopathies (neurodegenerative diseases hallmarked by aberrant endogenous brain rhythms).
Rhythmic sensory stimulation (flicker) has many applications: From human vision and cognitive neuroscience research to visual impairment diagnostics. Aberrant responses to flicker stimulation have also been used as diagnostic tools in clinical neuroscience (e.g. schizophrenia, mood disorders, epilepsy, migraine). Why do responses to alpha flicker predict effectiveness of medication? Why can alpha flicker trigger epileptiform dynamics? Answers to these questions require understanding the neural mechanisms underlying responses to rhythmic stimulation.
Despite a long history and applications, the neural mechanisms by which rhythmic sensory stimuli interact with and modulate endogenous brain rhythms, are unknown. The objectives of this project were to: (1) measure the interactions between exogenous rhythms and endogenous brain oscillations at the level they are generated using high-density laminar probes that enable recording from hundreds of neurons across cortical laminae; (2) optogenetically identify and manipulate different classes of neurons. This fundamental research knowledge on interactions between exogenous and endogenous rhythms holds realistic promise in the clinical domain for diagnosis and therapeutic interventions of oscillopathies (neurodegenerative diseases hallmarked by aberrant endogenous brain rhythms).
To achieve the objectives, we performed several experiments and performed new analyses on previously collected data.
In humans, resonance phenomena (increased amplitude response to certain rhythmic visual stimulation frequencies) have been studied exclusively at the cortical level. However, the primary visual cortex (V1) receives its primary input from dorsolateral geniculate nucleus of the thalamus (dLGN) and also sends back projections to dLGN, which highly outnumber feedforward connections. Thus, the resonance phenomena observed at the level of V1 could be a result of bidirectional interaction in corticothalamic networks. To address this possibility, we performed simultaneous recordings in the mouse V1 and dLGN by inserting laminar probe under an angle relative to the cortical surface to target both brain areas.
We found that resonance frequencies are highly preserved from humans to mice, with the same characteristic peaks with slight differences in the exact frequencies (in mice on average: 8 Hz, 15 Hz, 33 Hz; in humans we found on average: 10 Hz, 15 Hz, 45 Hz). These findings validate the use of mouse as a model for understanding mechanisms underlying generation of cortical oscillations and cross-frequency interactions. Additional resonance rhythm in the theta band (~5 Hz) has been also observed in mice. By combining animal motion and neural data analysis, we found that resonance in theta turned out to be related to whisking and breathing of the animal.
Although some studies have shown the effects of 40 Hz flicker stimulation in higher cortical regions (prefrontal cortex and CA1 of the hippocampus) in case of Alzheimer’s disease, it is generally assumed that rhythmic visual stimulation effects are constrained to visual system. In re-analysis of wide-field imaging data that I previously collected, we tested whether rhythmic visual stimulation effects are observable beyond the visual system. Comparison of spatial extent of responses across different flicker frequencies revealed that flicker frequencies below 11 Hz elicited responses beyond visual areas (auditory and somatosensory areas), thus providing some support for flicker effects outside V1. As part of the collaboration, I also led the project on resonance frequencies in the somatosensory cortex using EEG in humans, the results of which are published in high-impact factor journal (Journal of Neuroscience).
Recorded mouse electrophysiology data are currently analyzed and results from re-analyzed data are in the final stages of publication preparation for high-profile peer reviewed journal and have been presented at multiple international conferences and invited talks (Society for Neuroscience Meeting, International Conference of Cognitive Neuroscience, European Visual Cortex Meeting).
In humans, resonance phenomena (increased amplitude response to certain rhythmic visual stimulation frequencies) have been studied exclusively at the cortical level. However, the primary visual cortex (V1) receives its primary input from dorsolateral geniculate nucleus of the thalamus (dLGN) and also sends back projections to dLGN, which highly outnumber feedforward connections. Thus, the resonance phenomena observed at the level of V1 could be a result of bidirectional interaction in corticothalamic networks. To address this possibility, we performed simultaneous recordings in the mouse V1 and dLGN by inserting laminar probe under an angle relative to the cortical surface to target both brain areas.
We found that resonance frequencies are highly preserved from humans to mice, with the same characteristic peaks with slight differences in the exact frequencies (in mice on average: 8 Hz, 15 Hz, 33 Hz; in humans we found on average: 10 Hz, 15 Hz, 45 Hz). These findings validate the use of mouse as a model for understanding mechanisms underlying generation of cortical oscillations and cross-frequency interactions. Additional resonance rhythm in the theta band (~5 Hz) has been also observed in mice. By combining animal motion and neural data analysis, we found that resonance in theta turned out to be related to whisking and breathing of the animal.
Although some studies have shown the effects of 40 Hz flicker stimulation in higher cortical regions (prefrontal cortex and CA1 of the hippocampus) in case of Alzheimer’s disease, it is generally assumed that rhythmic visual stimulation effects are constrained to visual system. In re-analysis of wide-field imaging data that I previously collected, we tested whether rhythmic visual stimulation effects are observable beyond the visual system. Comparison of spatial extent of responses across different flicker frequencies revealed that flicker frequencies below 11 Hz elicited responses beyond visual areas (auditory and somatosensory areas), thus providing some support for flicker effects outside V1. As part of the collaboration, I also led the project on resonance frequencies in the somatosensory cortex using EEG in humans, the results of which are published in high-impact factor journal (Journal of Neuroscience).
Recorded mouse electrophysiology data are currently analyzed and results from re-analyzed data are in the final stages of publication preparation for high-profile peer reviewed journal and have been presented at multiple international conferences and invited talks (Society for Neuroscience Meeting, International Conference of Cognitive Neuroscience, European Visual Cortex Meeting).
The findings of resonance frequencies in V1 and thalamus demonstrated during MSCA fellowship challenge the established idea that V1 is unable to follow high frequency exogenous rhythms. Another novel finding resulted from a collaboration with theoretical neuroscientist Dr. Michael Rule (Cambridge University, UK) that has started as part of Dissemination strategy (Symposium at Vision Science of Art 2022 conference). The result of collaboration is a formal mathematical description of spatiotemporal propagation and interaction of flicker-induced cortical waves that I have found in the empirical data. The findings of this collaboration are valuable both to experimental and theoretical neuroscience community as it describes a new principle on how flicker-induced perceptual patterns can form. This is documented in the manuscript.
As a valuable training grant, MSCA fellowship allowed me to acquire a set of new skills and competences: Learning and implementing rodent electrophysiology techniques (from surgeries and in vivo laminar recordings in behaving mice to high-dimensional data analyses). All these techniques were completely new to me prior to MSCA fellowship, as in my previous research I used M/EEG and fMRI recordings in humans and non-invasive widefield imaging recordings in mice. It is exceedingly rare for researchers to move from research at one spatial scale to another (from human M/EEG to rodent laminar electrophysiology), which I was able to do with MSCA support. In the process, I also improved the experimental setup at the host institute and contributed to online knowledge-share platform dedicated to Neuropixels recordings and data analysis (ephyswiki.org).
As a valuable training grant, MSCA fellowship allowed me to acquire a set of new skills and competences: Learning and implementing rodent electrophysiology techniques (from surgeries and in vivo laminar recordings in behaving mice to high-dimensional data analyses). All these techniques were completely new to me prior to MSCA fellowship, as in my previous research I used M/EEG and fMRI recordings in humans and non-invasive widefield imaging recordings in mice. It is exceedingly rare for researchers to move from research at one spatial scale to another (from human M/EEG to rodent laminar electrophysiology), which I was able to do with MSCA support. In the process, I also improved the experimental setup at the host institute and contributed to online knowledge-share platform dedicated to Neuropixels recordings and data analysis (ephyswiki.org).