a-protocol-for-uncovering-neural-mechanisms-neurotherapeutic-effects

A Protocol For Uncovering Neural Mechanisms Of Neurotherapeutic Effects On Electroencephalography Using The Human Neocortical Neurosolver

Electroencephalography (EEG) and electrophysiological methods provide millisecond-resolution biomarkers for central nervous system disorders and are ...

Brown University

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

Thalamocortical control of propofol phase-amplitude coupling.

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brain stem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low-beta and slow rhythm, as well as their interactions. Our model suggests that propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta-frequency spiking in thalamus (C-state), whereas in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha colocalizes to the peak of the slow oscillation; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brain stem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state. GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We constructed a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brain stem neuromodulation.

Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model.

Electroencephalography (EEG) and electrophysiology methods provide millisecond resolution biomarkers for central nervous system disorders and are used to assess treatment-related effects. However, lack of understanding about the neural mechanisms generating such biomarkers impedes the development of diagnostics and therapeutics based on these signals. The Human Neocortical Neurosolver (HNN) is an open-source biophysical modeling software that connects localized EEG biomarkers to their multi-scale neural generators. This protocol demonstrates a hypothesis-driven workflow using HNN to test possible neural mechanisms of neurotherapy-induced EEG biomarkers by optimizing parameters to achieve a fit between simulated and empirical current source waveforms. Corresponding multi-scale cell- and circuit-level activity can then be visualized and quantified, providing validation targets for model predictions in follow up empirical studies. An example is provided which shows how to examine the generating mechanisms of the early event-related potential (ERP) components of an auditory evoked response (P1, N1 and P2) and to assess changes following neural circuit modification due to neurotherapeutic administration. This protocol demonstration enables scientists to design simulation experiments to develop testable predictions on how EEG biomarkers reflect neural circuit mechanisms of example therapeutics. A similar protocol can be applied to study disease mechanisms or other therapies.

Article	Year
Thalamocortical control of propofol phase-amplitude coupling. PLoS computational biology\| PubMed ID: 29227992	2017
Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model. Journal of neurophysiology\| PubMed ID: 37314079	2023
Uncovering putative neural mechanisms of neurotherapeutic impacts on EEG using the Human Neocortical Neurosolver. bioRxiv : the preprint server for biology\| PubMed ID: 42039506	2026

Austin E. Soplata

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