Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization

Monai, Hiromu; Koketsu, Shinnosuke; Shinohara, Yuta; Ueki, Takatoshi; Kusk, Peter; Hauglund, Natalie L.; Samson, Andrew J.; Nedergaard, Maiken; Hirase, Hajime

doi:10.1038/s41598-021-87609-w

Cited by 13 publications

(14 citation statements)

References 68 publications

(58 reference statements)

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“…In this computational review paper, we showed that tDCS-evoked hemodynamic response and pupil dilation can be related in healthy individuals, postulated to be subserved by arousal mechanisms, and future studies should investigate this relationship in disorders of consciousness, including Alzheimer’s disease. Moreover, subject-specific interactions [ 80 ] between the tDCS-evoked LC-NE activity and interstitial potassium concentration, which can modulate neurovascular coupling [ 9 ], could provide insights into the interindividual variability in the effects of tES [ 6 ]. Furthermore, tES-evoked increase in energy demand can uncover abnormalities [ 7 ] of cerebral metabolism that can be elucidated through system analysis of the neuroimaging data.…”

Section: Discussionmentioning

confidence: 99%

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Arora

Dutta

2022

Brain Sciences

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Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) are increasingly demonstrated by the large variability in the effects of tES. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not “realistic” in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization at the point of care is proposed in this perspective article based on systems analysis of the neurovascular effects of tES. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). During tES, the transient sensations can have arousal effects on the hemodynamics, so we present a healthy case series for black-box modeling of fNIRS–pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a one-step Granger cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p < 0.05). Moreover, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed the HbT response to be significantly different (paired-samples t-test, p < 0.05) between the ipsilesional and contralesional hemispheres for primary motor cortex tDCS and cerebellar tDCS, which was subserved by the smooth muscle cells. Here, our opinion is that various physiological pathways subserving the effects of tES can lead to state–trait variability, which can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced-dimensions model and a stochastic, derivative-free covariance matrix adaptation evolution strategy. We conclude from our computational analysis that human-in-the-loop optimization of the effects of tES at the point of care merits investigation in future studies for reducing inter-subject and intra-subject variability in neuromodulation.

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Section: Discussionmentioning

confidence: 99%

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Arora

Dutta

2022

Brain Sciences

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“…Moreover, glial cells contribute to intracellular calcium rise in neurons ( 50 ), including in conditions where oxygen is lacking ( 51 ). Finally, adrenergic modulation of astrocyte activity after cortical spreading depolarization accelerates the recovery of neural activity ( 52 ). In future experiments in transgenic zebrafish lines, labeling glial cells ( 53 , 54 ) will help determine their contribution to heat-induced spreading depolarization.…”

Section: Discussionmentioning

confidence: 99%

Brain dysfunction during warming is linked to oxygen limitation in larval zebrafish

Andreassen

Hall

Khatibzadeh

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the physiological mechanisms that limit animal thermal tolerance is crucial in predicting how animals will respond to increasingly severe heat waves. Despite their importance for understanding climate change impacts, these mechanisms underlying the upper thermal tolerance limits of animals are largely unknown. It has been hypothesized that the upper thermal tolerance in fish is limited by the thermal tolerance of the brain and is ultimately caused by a global brain depolarization. In this study, we developed methods for measuring the upper thermal limit (CT max ) in larval zebrafish ( Danio rerio ) with simultaneous recordings of brain activity using GCaMP6s calcium imaging in both free-swimming and agar-embedded fish. We discovered that during warming, CT max precedes, and is therefore not caused by, a global brain depolarization. Instead, the CT max coincides with a decline in spontaneous neural activity and a loss of neural response to visual stimuli. By manipulating water oxygen levels both up and down, we found that oxygen availability during heating affects locomotor-related neural activity, the neural response to visual stimuli, and CT max . Our results suggest that the mechanism limiting the upper thermal tolerance in zebrafish larvae is insufficient oxygen availability causing impaired brain function.

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“…In this computational review paper, we showed that tDCS-evoked hemodynamic response and pupil dilation can be related in healthy individuals, postulated to be subserved by arousal mechanisms, where future studies need to investigate this relationship in disorders of consciousness including Alzheimer's disease. Moreover, subject-specific interaction [86] between the tDCS-evoked LC-NE activity and the postulated increase in the interstitial potassium concentration, which can modulate neurovascular coupling [31], can provide insights into the inter-individual variability in tES effects [6]. Then, tES-evoked increase in energy demand can uncover abnormalities [7] of cerebral metabolism that can be elucidated with system analysis of the neuroimaging data.…”

Section: Discussionmentioning

confidence: 99%

Human-In-The-Loop Optimization of Transcranial Electrical Stimulation Effects: A Computational Perspective Based on Systems Analysis

Arora¹,

Dutta²

2022

Preprint

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Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) is increasingly demonstrated in large variability in the tES effects. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not ‘realistic’ in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization is proposed in this perspective article based on an extensive systems analysis of the tES neurovascular effects. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). tES effects in the 0 Hz to 0.05 Hz range can also be measured with functional magnetic resonance imaging (fMRI)-tDCS data with a maximum TR=10sec. Therefore, we investigated an open-source fMRI-tDCS dataset that used a TR=3.36sec. We found that both the anodal tDCS condition and sham tDCS condition had similar Finite Impulse Response at the region of interest underlying the anode and a remote location, which indicated a global hemodynamic effect of sham tDCS beyond the intended transient sensations. Here, transient sensations can have arousal effects on the hemodynamics so we conducted a healthy case series for black box modeling of fNIRS-pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a 1-step Granger-cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p<0.05). Also, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed HbT response to be significantly different (paired-sample t-test, p<0.05) between the ipsilesional and the contralesional hemisphere for primary motor cortex tDCS and cerebellar tDCS which was subserved by the smooth muscle cells. Here, our perspective is that various physiological pathways subserving tES effects can lead to state-trait variability that can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced dimension model and a stochastic, derivative-free Covariance Matrix Adaptation Evolution Strategy. Future studies need to investigate human-in-the-loop optimization of tES for reducing inter-subject and intra-subject variability in tES effects.

show abstract

Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization

Cited by 13 publications

References 68 publications

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Brain dysfunction during warming is linked to oxygen limitation in larval zebrafish

Human-In-The-Loop Optimization of Transcranial Electrical Stimulation Effects: A Computational Perspective Based on Systems Analysis

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