Lydia Marks

Abstract Cortical stimulation with single pulses is a common technique in clinical practice and research. However, we still do not understand the extent to which it engages subcortical circuits which contribute to the associated evoked potentials (EPs). Here we find that cortical stimulation generates remarkably similar EPs in humans and mice, with a late component similarly modulated by the subject’s behavioral state. We optogenetically dissect the underlying circuit in mice, demonstrating that the late component of these EPs is caused by a thalamic hyperpolarization and rebound. The magnitude of this late component correlates with the bursting frequency and synchronicity of thalamic neurons, modulated by the subject’s behavioral state. A simulation of the thalamo-cortical circuit highlights that both intrinsic thalamic currents as well as cortical and thalamic GABAergic neurons contribute to this response profile. We conclude that the cortical stimulation engages cortico-thalamo-cortical circuits highly preserved across different species and stimulation modalities. Graphical abstract

Bursting

Cortical neurons

Thalamic stimulator

10.1101/2024.01.31.578243

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Citations (4)

Reviewer #1 (Public Review): Cortico-thalamo-cortical interactions modulate electrically evoked EEG responses in mice

Leslie D. Claar Irene Rembado Jacqulyn R. Kuyat Simone Russo Lydia Marks

Perturbational complexity analysis predicts the presence of consciousness in volunteers and patients by stimulating the brain with brief pulses, recording electroencephalographic (EEG) responses, and computing their spatiotemporal complexity. We examined the underlying neural circuits in mice by directly stimulating cortex while recording with EEG and Neuropixels probes during wakefulness and isoflurane anesthesia. When mice are awake, stimulation of deep cortical layers reliably evokes locally a brief pulse of excitation, followed by a bi-phasic sequence of 120 ms profound off period and a rebound excitation. A similar pattern, partially attributed to burst spiking, is seen in thalamic nuclei, and is associated with a pronounced late component in the evoked EEG. We infer that cortico-thalamo-cortical interactions drive the long-lasting evoked EEG signals elicited by deep cortical stimulation during the awake state. The cortical and thalamic off period and rebound excitation, and the late component in the EEG, are reduced during running and absent during anesthesia.

Burst suppression

10.7554/elife.84630.2.sa1

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Local microcircuits underlying EEG responses to electrical stimulation across conscious and unconscious states in mice

Brain stimulation (2023)

Simone Russo Irene Rembado Leslie D. Claar Lydia Marks Christof Koch

Abstract Event-related potentials (ERPs), derived from electroencephalographic (EEG) signals by temporal averaging, provide a non-invasive and direct measure of neural activity in response to a repeated stimulus. Direct brain stimulations elicit ERPs whose features depend on both the stimulated cortical area (Rosanova M., 2009; Parmigiani, S., 2022) and the brain state (Massimini M., 2005; Casali A.G., 2013; Claar, Rembado, 2022). However, our understanding of the underlying neural microcircuits remains limited. To fill this gap, we monitored 102-103 individual, well-separated, single units and local field potentials using multiple Neuropixels probes (Siegle J., 2021) with concurrent EEG recordings from up to 30 electrodes below the scalp of the mouse while applying electrical stimulation in different cortical areas during different brain states. We characterized the ERP components (magnitude and timing of EEG positivity and negativity) in terms of changes of spiking properties (spike firing rate, spike timing, thalamic bursting), and laminar synaptic currents through current source density analysis. The same characterization will be extended to unconscious states induced by isoflurane and urethane. Our preliminary results reveal that the initial component of these ERPs is unaffected by brain state, while the state-dependent features build up over time by engaging the thalamocortical network. We infer that the response features unaffected by anesthetics are likely to result from intrinsic feedforward characteristics of the stimulated area. Conversely, the response features affected by anesthetics may reflect operational properties of the stimulated area. To clarify the mechanistic origins of ERPs, we link the macroscale EEG dynamics with the underlying microscale dynamics. Research Category and Technology and Methods Translational Research: 21. Neurophysiology Keywords: Consciousness, Electrical stimulation, EEG, Neuropixel

Local field potential

Bursting

Burst suppression

Stimulus (psychology)

Microstimulation

10.1016/j.brs.2023.01.678

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Reviewer #1 (Public Review): Cortico-thalamo-cortical interactions modulate electrically evoked EEG responses in mice

Leslie D. Claar Irene Rembado Jacqulyn R. Kuyat Simone Russo Lydia Marks

Perturbational complexity analysis predicts the presence of consciousness in volunteers and patients by stimulating the brain with brief pulses, recording electroencephalographic (EEG) responses, and computing their spatiotemporal complexity. We examined the underlying neural circuits in mice by directly stimulating cortex while recording with EEG and Neuropixels probes during wakefulness and isoflurane anesthesia. When mice are awake, stimulation of deep cortical layers reliably evokes locally a brief pulse of excitation, followed by a bi-phasic sequence of 120 ms profound off period and a rebound excitation. A similar pattern, partially attributed to burst spiking, is seen in thalamic nuclei, and is associated with a pronounced late component in the evoked EEG. We infer that cortico-thalamo-cortical interactions drive the long-lasting evoked EEG signals elicited by deep cortical stimulation during the awake state. The cortical and thalamic off period and rebound excitation, and the late component in the EEG, are reduced during running and absent during anesthesia.

Burst suppression

10.7554/elife.84630.1.sa1

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Reviewer #2 (Public Review): Cortico-thalamo-cortical interactions modulate electrically evoked EEG responses in mice

Leslie D. Claar Irene Rembado Jacqulyn R. Kuyat Simone Russo Lydia Marks

Perturbational complexity analysis predicts the presence of consciousness in volunteers and patients by stimulating the brain with brief pulses, recording electroencephalographic (EEG) responses, and computing their spatiotemporal complexity. We examined the underlying neural circuits in mice by directly stimulating cortex while recording with EEG and Neuropixels probes during wakefulness and isoflurane anesthesia. When mice are awake, stimulation of deep cortical layers reliably evokes locally a brief pulse of excitation, followed by a bi-phasic sequence of 120 ms profound off period and a rebound excitation. A similar pattern, partially attributed to burst spiking, is seen in thalamic nuclei, and is associated with a pronounced late component in the evoked EEG. We infer that cortico-thalamo-cortical interactions drive the long-lasting evoked EEG signals elicited by deep cortical stimulation during the awake state. The cortical and thalamic off period and rebound excitation, and the late component in the EEG, are reduced during running and absent during anesthesia.

Burst suppression

10.7554/elife.84630.2.sa2

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Thalamic feedback shapes brain responses evoked by cortical stimulation in mice and humans

Brain stimulation (2025)

Simone Sarasso Leslie D. Claar Lydia Marks Giri P. Krishnan Giulia Furregoni

Brain stimulation

Cortical neurons

10.1016/j.brs.2024.12.127

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