Difference between revisions of "October 2026"

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'''AY '26-'27 Goals'''
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'''Lab Vision'''
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We explore mechanisms whereby anesthetics lead to amnesia, hypnosis (i.e. impaired behavioral responsiveness), immobility, and analgesia. We develop pharmacologic and device-based methods to modulate components of anesthesia non-invasively.
 +
 
 +
'''AY '26-'27 Goals → October Goals'''
 
*Submit a manuscript for publication
 
*Submit a manuscript for publication
 
**Meet w/ Nina
 
**Meet w/ Nina
 
**Identify two journals (plan A and plan B) to submit Brandon's study to. Understand their submission requirements. Write up the introduction for the study in LaTeX, formatted and tailored appropriately for each journal.
 
**Identify two journals (plan A and plan B) to submit Brandon's study to. Understand their submission requirements. Write up the introduction for the study in LaTeX, formatted and tailored appropriately for each journal.
 +
**Feasability study of SCD-PV
 +
**Lit review and, if novel, data sharing agreement for Methohexital
 +
 
*Submit RISE 1 application
 
*Submit RISE 1 application
 
**Narrow down research directions and goals
 
**Narrow down research directions and goals
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**Identify mentors and institutional resources
 
**Identify mentors and institutional resources
 
*Identify additional funding sources and apply
 
*Identify additional funding sources and apply
 +
 
*Start recruiting a research team
 
*Start recruiting a research team
  
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==10/2==
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==10/2 Summary==
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*E-mailed slides to Nina and followed up on study. It is currently paused due to a bupivacaine shortage.
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*E-mailed slides to Nina and followed up on study. It is currently paused due to a hyperbaric PF bupivacaine shortage at OHSU.
−
*Texted Brandon about which journals to submit to. '''1st choice: A&A, 2nd choice: Journal for Obstetric Anesthesia'''
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*Texted Brandon about which journals to submit to. 1st choice: A&A, 2nd choice: Journal for Obstetric Anesthesia
−
*Does TIVA prevent cancer recurrence? Head of Huntsman anesthesia did a cancer anesthesia fellowship and researched this a bit. Though he's now burned out on research, he's the guy to talk to about what's already been done or not.
+
*Does TIVA prevent cancer recurrence? Ty Call, head of Huntsman anesthesia, did a cancer anesthesia fellowship and researched this a bit. Though he's now burned out on research, he's the guy to talk to about what's already been done or not.
−
*Hamilton and I talked about why ketamine causes lasting changes in the brain long after the drug is gone. Is it a change to a gap junction network? '''Is it anti-inflammatory circulating EVs?'''. There are three papers on MedLine related to ketamine and EVs, none of which look (anti-)inflammatory molecules. Do circulating EVs after propofol anesthetic also contain the inflammatory cytokines that are seen after isoflurane?
+
*Hamilton and I talked about why ketamine causes lasting changes in the brain long after the drug is gone. Is it a change to a gap junction network? '''Is it anti-inflammatory circulating EVs?'''. There are three papers on MedLine related to ketamine and EVs, none of which look at (anti-)inflammatory molecules. '''Do circulating EVs after propofol anesthetic also contain the inflammatory cytokines that are seen after isoflurane?'''
 +
 
 +
==10/6 Summary==
 +
*Pitched multi-centre trial to Brandon. E-mailed slides in .ppt format to Nina.
 +
*Met w/ Norm about depression research (Brian Mickey and Grace Lee) and promotion requirements (Harriet Hopf). '''Need to read this paper about ketamine having an active metabolite that sticks around, explaining its sustained antidepressant effects''' ([https://scholar.googleusercontent.com/scholar.bib?q=info:oxmvfF2RMfcJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixuUERc:ACTRDVEAAAAAas-SCRfDvqsYSFStZqKmI5mpZP0&scisig=ACTRDVEAAAAAas-SCWl_hrwNxs7LrCdW_sSZWZk&scisf=4&ct=citation&cd=-1&hl=en Nature paper]).
 +
*Lit review of Yohimbine and Naloxone effects on EEG.
 +
*Dug through supplement of 2026 A&A paper to find which anesthetics are most selective for which receptors ''in vitro''.
 +
*Thought about Jellyfish, Corral, Hydra
 +
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC12998346/ Remimazolam targets]: the theoretical initial target concentration of remimazolam may be 0.1 µg/mL for light sedation, 0.2 µg/mL for moderate sedation, and 0.3 µg/mL for deep sedation in elderly patients (70 years), and 1.5 or 2 times those concentrations in middle-aged (45 years) or young adult (20 years) patients. Dose adjust upwards by 10% in females, down by 20% in obesity or ASA III/IV.
 +
 
 +
==10/14 Summary==
 +
*Lab meeting
 +
**'''What are MER transitions?'''
 +
**'''DECODE problem is how to detect neural activity of subcortical sources from scalp EEG?''' They are currently throwing different things at it but from a single EEG electrode.
 +
**Trying to figure out frequency and phase response of the SedLine
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**Some seriously impressive GUIs
 +
 
 +
*Call w/ Christian
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**Christian has Wednesday/Thursday off every week, his third NCD is variable.
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**Christian to add me to two protocols for collecting human EEG data
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***SedLine deferred consent retrospective study (PI is Norm Taylor)
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***DECODE (neurosurgery, SEEG-electrodes, LFP along the whole lead, individual neurons at the tips), neuromodulation using Ripple (lab-grade, non-FDA approved device), different protocol (COMPASS) where we do need to consent patients
 +
**[https://www.tidalneuro.com/# TidalNeuro] is the start-up and we are developing Ripple-grade wireless device
 +
**Need access to files. Figure out how to connect to VPN and '''ask Cameron Jacobson for access to local SAND lab web disk'''.
 +
**GitHub can pull functions to work on data from the web disk. '''Ask Srdjan to add me to the main branch.'''
 +
**FAER, IARS, RISE. Kristen Kinjo added me to her list to inform of possible funding opportunities.
 +
**Uploaded CITI competency to ERICA system, CC'd Christian
 +
**Meet next Tuesday to demo Ripple hardware with live intra-op recordings.
 +
**EEG workshop at February meeting. Christian shared 16 PEACE competencies to start prepping. We could either split it up to each do 8 (preferable), or we could cover all 16, but on different devices.
 +
 
 +
*Reached out to Grace about ketamine research (OB vs. general surgery population, decreasing incidence of postpartum/post-op depression w/ single dose of ketamine).
 +
 
 +
*Thinking about propofol mechanisms
 +
**'''Read all about GABA receptors in Principles of Neural Science'''
 +
**Optogenetics can control the activity of a genetically defined set of neurons to see if they are important for your topic of interest. e.g. express anion-conducting channelrhodopsins (ACRs, an inhibitory type of ChR) in α1β2γ2 GABA-R expressing neurons.
 +
***Could we use optogenetics to clarify whether certain non-canonical propofol target receptors (e.g. α4β2 nAChR, HCN1) are necessary or sufficient for its effects?
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***Assuming that α1β2γ2 GABA<sub>A</sub>R is the critical receptor, can we demonstrate which circuits play a critical role? As a starting point (from Brown's Part I):
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## Excitatory cortical pyramidal neurons
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## Galan-/GABA-ergic hypothalamic POA projections to monoaminergic brainstem nuclei: LC (NE), DR (5HT), vPAG (DA), TMN (His)
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## GABAergic neurons in the TRN (thalamic reticular nucleus)
 +
 
 +
* Who is doing patch clamp that could teach me or just do it? Coby has experience with ephys.
 +
 
 +
* Meeting with Hamilton
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** His lab specializes in light-sheet imaging and they have single neuron resolution where they can look at calcium currents (neuronal activity) in real time.
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** He mentioned that ''C. elegans'' don't have any histamine signaling natively. You can make animals that express histamine-gated chloride channels to inactivate channel expressing neurons when histamine is given exogenously. '''Look for a GABA<sub>A</sub>R His-Cl worm line.
 +
** He is going to send me some links to worm genetic databases, and some protocols for breeding and behavior.
 +
** I am going to read up on propofol mechanisms '''in worms''', and gap junctions before our next meeting on 10/29.
  
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===Mechanisms of Anesthesia===
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*IARS abstract submission deadline is 12/6 (methohexital, ketamine depression, SCD-PV)
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'''Big picture:''' understand the temporospatial changes in neural activity induced by various anesthetics. Can we recapitulate those with steerable, low latency, closed-loop non-invasive neuromodulation or use this knowledge to drive discovery of novel drugs?
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** SCD PV
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*High-throughput screen of anesthetics (and anesthetic reversal agents) in C.elegans. I could work in parallel in a different organism (e.g. yeast, jellyfish, hydra, sea anemones, corral, bacteria, plants, neuronal explants).
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*** Talk to a circulator/scrub RN with a lot of experience.
−
*Based on 30 years of in vitro studies (n>300), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.
+
*** Do we only have one model?
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*Some anesthetics ('''ketamine, dexmedetomidine, etomidate, benzos''') are fairly selective, but are rarely used as sole anesthetics.
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*** How long have we had that one model? What did we use before that?
−
**Ketamine binds to α4β4 nAChR w/ IC<sub>50</sub> of 0.144 uM, but has an IC<sub>50</sub> for the GluN1/N2C NMDAR of 0.338 uM.
+
*** Do the RNs track anywhere that the boots have been applied and to which legs?
−
**Dexmedetomidine binds to α<sub>2A</sub> AR w/ K<sub>D</sub> of 0.0014 uM and the M<sub>3</sub> mAChR w/ IC<sub>50</sub> of 0.001 uM.
+
*** Where in the flowsheets is last liquid intake listed?
−
**Etomidate binds to α1β2γ2 GABA<sub>A</sub>R w/ an EC<sub>50</sub> of 1.08 uM, but to I<sub>K(dr)</sub> with an IC<sub>50</sub> of 4.59 uM, and the α1 GlyR w/ an IC<sub>50</sub> of 5.37 uM.
+
** '''Methohexital'''
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**Midazolam binds to α1β2γ2 GABA<sub>A</sub>R w/ EC<sub>50</sub> of 0.041 uM, Na<sub>V</sub> (neuron) IC<sub>50</sub> of 0.074 uM, and nAChR (muscle) w/ IC<sub>50</sub> of 0.143 uM.
 
−
**Diazepam binds to α1β2γ2 GABA<sub>A</sub>R w/ EC<sub>50</sub> of 0.07 uM.
 
−
**Sevoflurane binds to K<sub>v</sub>1.2 w/ EC<sub>50</sub> of 0.0097 mM.
 
  
−
*[https://scholar.googleusercontent.com/scholar.bib?q=info:dK96wvRnWFAJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixESwUs:ACTRDVEAAAAAasUU2UsAEqSgPmvYJRTMHcZKb4s&scisig=ACTRDVEAAAAAasUU2a34RqVYzDaWRdbVsL76Mk4&scisf=4&ct=citation&cd=-1&hl=en 2026 A&A paper] argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABA<sub>A</sub>R receptor.
+
==Mechanisms of Anesthesia==
−
*'''Are there pharmacological inhibitors with receptor specificity? When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA<sub>A</sub>R inhibitor? Could you do optogenetic location-specific inducible receptor knockdowns? Do model organisms already exist?'''
+
*High-throughput screen of anesthetics (and anesthetic reversal agents) in ''C.elegans''.
 +
===Promiscuous Molecular Targets===
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*[https://scholar.googleusercontent.com/scholar.bib?q=info:dK96wvRnWFAJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixJyYaI:ACTRDVEAAAAAasZ0eaKpU14jFRxgeJubQZ-AUJs&scisig=ACTRDVEAAAAAasZ0eT0zDfaBVoegO8FEa7bX0-A&scisf=4&ct=citation&cd=-1&hl=en 2026 A&A paper] argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABA<sub>A</sub>R receptor. Based on 30 years of in vitro studies (n>330), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.
 +
*According to this paper, some anesthetics (i.e. ketamine, dexmedetomidine, etomidate, benzos) are fairly selective, but are rarely used as sole anesthetics. Below, I list each of the ''in vitro'' binding affinities of these "selective" anesthetics, up until there is a change of one order of magnitude or greater for the next receptor.
 +
**Ketamine binds
 +
***α4β4 nAChR, IC<sub>50</sub> 0.144 uM
 +
***GluN1/N2C NMDAR, IC<sub>50</sub> 0.338 uM
 +
**Dexmedetomidine binds
 +
***α<sub>2A</sub> AR, K<sub>D</sub> 0.0014 uM
 +
***M<sub>3</sub> mAChR, IC<sub>50</sub> 0.001 uM
 +
**Etomidate binds
 +
***α1β2γ2 GABA<sub>A</sub>R, EC<sub>50</sub> 1.08 uM
 +
***I<sub>K(dr)</sub>, IC<sub>50</sub> 4.59 uM
 +
***α1 GlyR, IC<sub>50</sub> 5.37 uM
 +
**Midazolam binds
 +
***α1β2γ2 GABA<sub>A</sub>R, between the α1 and γ2 subunits, EC<sub>50</sub> 0.041 uM
 +
***Na<sub>V</sub> (neuron), IC<sub>50</sub> 0.074 uM
 +
***nAChR (muscle), IC<sub>50</sub> 0.143 uM
 +
**'''Diazepam''' binds α1β2γ2 GABA<sub>A</sub>R, EC<sub>50</sub> 0.07 uM
 +
**'''Sevoflurane''' binds K<sub>v</sub>1.2, EC<sub>50</sub> 0.0097 mM
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*Some common anesthetics that are less selective, or not characterized in the paper
 +
**Propofol binds to α4β2 nAChR with IC<sub>50</sub> of 3.13 uM, HCN1 receptors with IC<sub>50</sub> of 4.19 uM, and α1β2γ2 with EC<sub>50</sub> of 5.44 uM.
 +
**Remimazolam binds GABA<sub>A</sub> receptors [https://scholar.googleusercontent.com/scholar.bib?q=info:ZcRExfhIAgQJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixJ14Lg:ACTRDVEAAAAAasZz-Lg_XypnrGdHd1YvgyClzzA&scisig=ACTRDVEAAAAAasZz-GKPI-Z0ueEzxZoNZQpLFsU&scisf=4&ct=citation&cd=-1&hl=en non-selectively] (i.e. αxβ2γ2)
 +
====Rx Probing Anesthetic-Receptor Interactions====
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*'''Are there pharmacological agents with effects complementary to those of anesthetics with receptor specificity? Do they cross the blood brain barrier? Search [https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL63354/ ChEMBL].'''
 +
{| class="wikitable sortable"
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|+ Potential Anesthetic Antagonists
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|-
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! Receptor !! Anesthetic Antagonist !! Off-Target Effects? !! Crosses BBB !! Approved for Humans
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|-
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| α1β2γ2 GABA<sub>A</sub>R || methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) || Example || Example || Example
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|-
 +
| α1β2γ2 GABA<sub>A</sub>R || Flumazenil (competitive inhibitor of benzodiazepine binding) || protoporphyrin IX, α2,3,5, γ3 || yes || yes
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|-
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| α1β2γ2 GABA<sub>A</sub>R || Diazepam (potentiates GABA's effects) || ??? || yes || yes
 +
|-
 +
| HCN1 || Example || Example || Example || Example
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|-
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| α4β4 nAChR || Example || Example || Example || Example
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|-
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| GluN1/N2C NMDAR || Example || Example || Example || Example
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|-
 +
| α<sub>2A</sub> AR || Example || Example || Example || Example
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|-
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| M<sub>3</sub> mAChR || Example || Example || Example || Example
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|-
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| K<sub>v</sub>1.2 || Example || Example || Example || Example
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|}
 +
*When given at equipotent doses with propofol, how do diazepam's behavioral effects differ? How are they the same?
 +
*Would flumazenil block propofol's effect on the GABA<sub>A</sub>R, despite binding at a different site? What to make of the off-target effects?
 +
*'''When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA<sub>A</sub>R inhibitor?'''
 +
 
 +
====Genetic Probing of Anesthetic-Receptor Interactions====
 +
*'''Are there genetic KO/KD or optogenetic tools available for location-specific inducible receptor knockdowns?'''
 +
**Optogenetics has been used to inhibit neurons ([https://scholar.googleusercontent.com/scholar.bib?q=info:E5ci0TmjTyUJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixuAMnI:ACTRDVEAAAAAas-GKnJgn-bjNlsNLChcKv4my2s&scisig=ACTRDVEAAAAAas-GKgEqKyhrCyTgoY7wITcfbIk&scisf=4&ct=citation&cd=-1&hl=en Boyden] [https://scholar.googleusercontent.com/scholar.bib?q=info:5bB4NZj9XJwJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixuAD4Q:ACTRDVEAAAAAas-GF4QQx1MktzR7KJjHy7lxqtc&scisig=ACTRDVEAAAAAas-GF0WwYhYzurZCN_BZ43PKYBA&scisf=4&ct=citation&cd=-1&hl=en Zhang]) and control motor responses in ''C. elegans'' ([https://scholar.googleusercontent.com/scholar.bib?q=info:DR_TtH156CwJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixuATj4:ACTRDVEAAAAAas-GVj4eXZwSNxuPraJTtvvWPi4&scisig=ACTRDVEAAAAAas-GVgi34VSVojs0nt7HO_YbU68&scisf=4&ct=citation&cd=-1&hl=en Nagel])
 +
**The effect of anion-conducting channelrhodopsins (ACRs) on the activity of the neuron is comparable to GABA<sub>A</sub> receptors.
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**'''Is the receptor, its components, or homologues of the gene expressed in different model organisms? What is the sequence similarity with human?'''
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**'''Search [https://flybase.org flybase], [https://www.informatics.jax.org/ MGI], [https://www.wormbase.org/ wormbase], [https://zfin.org/ zebra fish information network], [https://www.yeastgenome.org/ yeast genome database]'''
 +
*'''Where and by what cell types are these receptors expressed in the human brain?'''
 +
 
 +
===Phylogenetic Approach===
 +
*Are there organisms that are resistant to anesthetics? Search for 'weird' organisms that might yield something interesting. Prokaryotes (bacteria, archaea) and Eukaryotes (Protists, Plants, Animals, Fungi). Single cellular and Multicellular organisms. For resistant organisms, what is different about them?
 +
**Downsides of using 'weird' organisms is that there are relatively few genetic tools, antibodies, sparse literature, and few experts to consult.
 +
**Has anyone published behavioral assays for these organisms? How do you make an argument that a slime mold has been anesthetized?
 +
 
 +
===Heterodox Hypothesis===
 +
*If you can anesthetize single-celled organisms, are circuits irrelevant?
 
*Hamilton has a gap junction (network of gap junctions?) and some specific neurons that he think are a conserved mechanism of anesthesia. He wants to test this by doing a screen of a bunch of different anesthetics in WT and KO worms with a behavioral screening assay. He has a behavior rig that basically automatically records swimming speed. He wants to look for the EC50 of various anesthetics and see if that number is shifted with KO or KD of different gap junctions.
 
*Hamilton has a gap junction (network of gap junctions?) and some specific neurons that he think are a conserved mechanism of anesthesia. He wants to test this by doing a screen of a bunch of different anesthetics in WT and KO worms with a behavioral screening assay. He has a behavior rig that basically automatically records swimming speed. He wants to look for the EC50 of various anesthetics and see if that number is shifted with KO or KD of different gap junctions.
 
*Worms natively have a blue-light rhodopsin that triggers an aversion response where they turn around and go the opposite direction.
 
*Worms natively have a blue-light rhodopsin that triggers an aversion response where they turn around and go the opposite direction.
−
*'''Next call 10/14.'''
+
*'''Next call 10/29.'''
−
*What are the differences in mechanisms for amnesia, hypnosis, immobility, and analgesia?
 
  
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===CLAN===
+
==CLAN==
−
====Alpha entrainment analgesia study====
+
===Alpha entrainment analgesia study===
 
**Successfully entrain alpha. What were we doing wrong? '''Is there anything in the literature that can guide a protocol modification?'''
 
**Successfully entrain alpha. What were we doing wrong? '''Is there anything in the literature that can guide a protocol modification?'''
 
**Can I incorporate withdrawal thresholds?
 
**Can I incorporate withdrawal thresholds?
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**Power analysis based on pilot study
 
**Power analysis based on pilot study
 
**'''Systematic review and meta analysis'''
 
**'''Systematic review and meta analysis'''
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====EEG effects of anesthetic agents====
+
**Simulation of inhibitory neurons in the ACC expressing channelrhodopsin-2 resulted in a reduction of reflexive acute pain responses in mice.
 +
====EEG nociceptive signatures====
 +
*See Naloxone below for a start.
 +
*Increased delta power, decreased alpha power
 +
 
 +
===EEG effects of anesthetic agents===
 
Look at benzos, opioids, precedex, and their respective reversal agents. Also caffeine, methylphenidate, and methohexital. In MedLine, combine each agent with the search term Electroencephalography/ and add limits for Adults, Humans, and English. Which drugs are most target selective? What are their EEG effects?
 
Look at benzos, opioids, precedex, and their respective reversal agents. Also caffeine, methylphenidate, and methohexital. In MedLine, combine each agent with the search term Electroencephalography/ and add limits for Adults, Humans, and English. Which drugs are most target selective? What are their EEG effects?
 +
 
*Yohimbine = 9
 
*Yohimbine = 9
−
**Yohimbine stimulates NE release from the locus ceruleus (riba2005journalofneuroscience). It decreases latency of the P200 in ERPs, suggesting a possible improvement in selective attention to environmental stimuli (turetsky2002psychophysiology).
+
**[https://scholar.googleusercontent.com/scholar.bib?q=info:fsNWkeZCSbIJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixFS6M0:ACTRDVEAAAAAasVU8M0M2rRPHr1d2pSaadsm4Lc&scisig=ACTRDVEAAAAAasVU8HfZxQ1XxpvMM1ojNx9eP-I&scisf=4&ct=citation&cd=-1&hl=en 2005 paper] shows that yohimbine stimulates NE release from the locus ceruleus.
 +
**[https://scholar.googleusercontent.com/scholar.bib?q=info:NPHzQqLViIwJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixFTH1A:ACTRDVEAAAAAasVVB1CDE5QBE2zAuDf3PKcoA_8&scisig=ACTRDVEAAAAAasVVB4uG91jOECpycg8q_Qw7xls&scisf=4&ct=citation&cd=-1&hl=en 2002 article] suggests that norepinephrine modulates CNS mechanisms of selective attention to infrequent stimuli (decreased latency of the P200 in ERPs).
 +
**[https://scholar.googleusercontent.com/scholar.bib?q=info:KO4REQm8XqMJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixFTPCI:ACTRDVEAAAAAasVVJCL_1MxLv2DfWNft2NQUFqk&scisig=ACTRDVEAAAAAasVVJHXd8JmpJq1mJK9LvvLkMUw&scisf=4&ct=citation&cd=-1&hl=en 1994 paper] reported speeding of N1 and single-trial P3 data indicate that noradrenergic drugs affect processing of early (visual) information. Yohimbine's speeding of P3 without changing RT is consistent with neural net (parallel) simulations but not with a serial model.
 +
**[https://scholar.googleusercontent.com/scholar.bib?q=info:CKmYkp6VoecJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixFTWfM:ACTRDVEAAAAAasVVQfNNkcr6LbQjfDZSiqNM0uQ&scisig=ACTRDVEAAAAAasVVQc42XPXPbUqRB0TpQxxCArU&scisf=4&ct=citation&cd=-1&hl=en 1985 study] showed yohimbine enhanced noradrenaline release, increased stage 1 and REM sleep, but decreased the stages 2 and 3 + 4; increases of mobility during REM and non-REM sleep signified desynchronization.
 +
 
 
*Naloxone = 28
 
*Naloxone = 28
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:YopyTTOWoR4J:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixEwMIk:ACTRDVEAAAAAasU2KIlV-oVXI_S0Cxge-WxR1vc&scisig=ACTRDVEAAAAAasU2KF5bb9Uy5zxwkigBDdV8YHg&scisf=4&ct=citation&cd=-1&hl=en 2021 study] looking at 20 health male volunteers showed that the magnitude of nociceptive withdrawal reflexes (NWRs) together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated by opioids. In the cold-pressor test, increases in delta amplitude and decreases in alpha power were reversed by opioids.
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:YopyTTOWoR4J:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixEwMIk:ACTRDVEAAAAAasU2KIlV-oVXI_S0Cxge-WxR1vc&scisig=ACTRDVEAAAAAasU2KF5bb9Uy5zxwkigBDdV8YHg&scisf=4&ct=citation&cd=-1&hl=en 2021 study] looking at 20 health male volunteers showed that the magnitude of nociceptive withdrawal reflexes (NWRs) together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated by opioids. In the cold-pressor test, increases in delta amplitude and decreases in alpha power were reversed by opioids.
Line 57: Line 183:
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:kiQAbPT3ne4J:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixE-YHY:ACTRDVEAAAAAasU4eHaWHARVsiuxWMOZVq08ESE&scisig=ACTRDVEAAAAAasU4eOy6y55DPxGPOocOvD8eoSs&scisf=4&ct=citation&cd=-1&hl=en 1979 study] showed 10 or 20 mg of naloxone elicited a significant slowing of the average alpha frequency in healthy male volunteers
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:kiQAbPT3ne4J:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixE-YHY:ACTRDVEAAAAAasU4eHaWHARVsiuxWMOZVq08ESE&scisig=ACTRDVEAAAAAasU4eOy6y55DPxGPOocOvD8eoSs&scisf=4&ct=citation&cd=-1&hl=en 1979 study] showed 10 or 20 mg of naloxone elicited a significant slowing of the average alpha frequency in healthy male volunteers
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:5qCNpmwZQbcJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixE-eSs:ACTRDVEAAAAAasU4YSsTyLuHIH5b9wGEZyM2kdQ&scisig=ACTRDVEAAAAAasU4YYSUhyN7ikowAEcV6bNoh_M&scisf=4&ct=citation&cd=-1&hl=en 1979 study] reported that some of the analgesic effects of N2O can be reversed with naloxone 0.4 mg, as evidenced by electrical pain-evoked potentials.
 
**[https://scholar.googleusercontent.com/scholar.bib?q=info:5qCNpmwZQbcJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixE-eSs:ACTRDVEAAAAAasU4YSsTyLuHIH5b9wGEZyM2kdQ&scisig=ACTRDVEAAAAAasU4YYSUhyN7ikowAEcV6bNoh_M&scisf=4&ct=citation&cd=-1&hl=en 1979 study] reported that some of the analgesic effects of N2O can be reversed with naloxone 0.4 mg, as evidenced by electrical pain-evoked potentials.
 +
 +
*Flumazenil = 94
 +
 
*Methylphenidate = 68
 
*Methylphenidate = 68
 +
 
*Methohexital = 80
 
*Methohexital = 80
−
*Flumazenil = 94
+
 
 
*Caffeine = 138
 
*Caffeine = 138
  
−
===CO2===
+
==CO2==
 
*Does permissive hypercapnia improve hemodynamic stability, improve oxygen delivery to tissues, deepen anesthesia, and speed recovery?
 
*Does permissive hypercapnia improve hemodynamic stability, improve oxygen delivery to tissues, deepen anesthesia, and speed recovery?
  
−
===Depression===
+
==Depression==
 
*Do ketamine, TIVA w/ propofol, TIVA w/ remimazolam, psychedelics, or burst suppression modulate the post-operative risk of depression?
 
*Do ketamine, TIVA w/ propofol, TIVA w/ remimazolam, psychedelics, or burst suppression modulate the post-operative risk of depression?
 +
 +
==Young Blood==

Latest revision as of 17:58, 15 October 2026

Lab Vision We explore mechanisms whereby anesthetics lead to amnesia, hypnosis (i.e. impaired behavioral responsiveness), immobility, and analgesia. We develop pharmacologic and device-based methods to modulate components of anesthesia non-invasively.

AY '26-'27 Goals → October Goals

  • Submit a manuscript for publication
    • Meet w/ Nina
    • Identify two journals (plan A and plan B) to submit Brandon's study to. Understand their submission requirements. Write up the introduction for the study in LaTeX, formatted and tailored appropriately for each journal.
    • Feasability study of SCD-PV
    • Lit review and, if novel, data sharing agreement for Methohexital
  • Submit RISE 1 application
    • Narrow down research directions and goals
    • Literature review to refine research aims
    • Identify mentors and institutional resources
  • Identify additional funding sources and apply
  • Start recruiting a research team

10/2 Summary

  • E-mailed slides to Nina and followed up on study. It is currently paused due to a hyperbaric PF bupivacaine shortage at OHSU.
  • Texted Brandon about which journals to submit to. 1st choice: A&A, 2nd choice: Journal for Obstetric Anesthesia
  • Does TIVA prevent cancer recurrence? Ty Call, head of Huntsman anesthesia, did a cancer anesthesia fellowship and researched this a bit. Though he's now burned out on research, he's the guy to talk to about what's already been done or not.
  • Hamilton and I talked about why ketamine causes lasting changes in the brain long after the drug is gone. Is it a change to a gap junction network? Is it anti-inflammatory circulating EVs?. There are three papers on MedLine related to ketamine and EVs, none of which look at (anti-)inflammatory molecules. Do circulating EVs after propofol anesthetic also contain the inflammatory cytokines that are seen after isoflurane?

10/6 Summary

  • Pitched multi-centre trial to Brandon. E-mailed slides in .ppt format to Nina.
  • Met w/ Norm about depression research (Brian Mickey and Grace Lee) and promotion requirements (Harriet Hopf). Need to read this paper about ketamine having an active metabolite that sticks around, explaining its sustained antidepressant effects (Nature paper).
  • Lit review of Yohimbine and Naloxone effects on EEG.
  • Dug through supplement of 2026 A&A paper to find which anesthetics are most selective for which receptors in vitro.
  • Thought about Jellyfish, Corral, Hydra
  • Remimazolam targets: the theoretical initial target concentration of remimazolam may be 0.1 µg/mL for light sedation, 0.2 µg/mL for moderate sedation, and 0.3 µg/mL for deep sedation in elderly patients (70 years), and 1.5 or 2 times those concentrations in middle-aged (45 years) or young adult (20 years) patients. Dose adjust upwards by 10% in females, down by 20% in obesity or ASA III/IV.

10/14 Summary

  • Lab meeting
    • What are MER transitions?
    • DECODE problem is how to detect neural activity of subcortical sources from scalp EEG? They are currently throwing different things at it but from a single EEG electrode.
    • Trying to figure out frequency and phase response of the SedLine
    • Some seriously impressive GUIs
  • Call w/ Christian
    • Christian has Wednesday/Thursday off every week, his third NCD is variable.
    • Christian to add me to two protocols for collecting human EEG data
      • SedLine deferred consent retrospective study (PI is Norm Taylor)
      • DECODE (neurosurgery, SEEG-electrodes, LFP along the whole lead, individual neurons at the tips), neuromodulation using Ripple (lab-grade, non-FDA approved device), different protocol (COMPASS) where we do need to consent patients
    • TidalNeuro is the start-up and we are developing Ripple-grade wireless device
    • Need access to files. Figure out how to connect to VPN and ask Cameron Jacobson for access to local SAND lab web disk.
    • GitHub can pull functions to work on data from the web disk. Ask Srdjan to add me to the main branch.
    • FAER, IARS, RISE. Kristen Kinjo added me to her list to inform of possible funding opportunities.
    • Uploaded CITI competency to ERICA system, CC'd Christian
    • Meet next Tuesday to demo Ripple hardware with live intra-op recordings.
    • EEG workshop at February meeting. Christian shared 16 PEACE competencies to start prepping. We could either split it up to each do 8 (preferable), or we could cover all 16, but on different devices.
  • Reached out to Grace about ketamine research (OB vs. general surgery population, decreasing incidence of postpartum/post-op depression w/ single dose of ketamine).
  • Thinking about propofol mechanisms
    • Read all about GABA receptors in Principles of Neural Science
    • Optogenetics can control the activity of a genetically defined set of neurons to see if they are important for your topic of interest. e.g. express anion-conducting channelrhodopsins (ACRs, an inhibitory type of ChR) in α1β2γ2 GABA-R expressing neurons.
      • Could we use optogenetics to clarify whether certain non-canonical propofol target receptors (e.g. α4β2 nAChR, HCN1) are necessary or sufficient for its effects?
      • Assuming that α1β2γ2 GABAAR is the critical receptor, can we demonstrate which circuits play a critical role? As a starting point (from Brown's Part I):
    1. Excitatory cortical pyramidal neurons
    2. Galan-/GABA-ergic hypothalamic POA projections to monoaminergic brainstem nuclei: LC (NE), DR (5HT), vPAG (DA), TMN (His)
    3. GABAergic neurons in the TRN (thalamic reticular nucleus)
  • Who is doing patch clamp that could teach me or just do it? Coby has experience with ephys.
  • Meeting with Hamilton
    • His lab specializes in light-sheet imaging and they have single neuron resolution where they can look at calcium currents (neuronal activity) in real time.
    • He mentioned that C. elegans don't have any histamine signaling natively. You can make animals that express histamine-gated chloride channels to inactivate channel expressing neurons when histamine is given exogenously. Look for a GABAAR His-Cl worm line.
    • He is going to send me some links to worm genetic databases, and some protocols for breeding and behavior.
    • I am going to read up on propofol mechanisms in worms, and gap junctions before our next meeting on 10/29.
  • IARS abstract submission deadline is 12/6 (methohexital, ketamine depression, SCD-PV)
    • SCD PV
      • Talk to a circulator/scrub RN with a lot of experience.
      • Do we only have one model?
      • How long have we had that one model? What did we use before that?
      • Do the RNs track anywhere that the boots have been applied and to which legs?
      • Where in the flowsheets is last liquid intake listed?
    • Methohexital

Mechanisms of Anesthesia

  • High-throughput screen of anesthetics (and anesthetic reversal agents) in C.elegans.

Promiscuous Molecular Targets

  • 2026 A&A paper argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABAAR receptor. Based on 30 years of in vitro studies (n>330), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.
  • According to this paper, some anesthetics (i.e. ketamine, dexmedetomidine, etomidate, benzos) are fairly selective, but are rarely used as sole anesthetics. Below, I list each of the in vitro binding affinities of these "selective" anesthetics, up until there is a change of one order of magnitude or greater for the next receptor.
    • Ketamine binds
      • α4β4 nAChR, IC50 0.144 uM
      • GluN1/N2C NMDAR, IC50 0.338 uM
    • Dexmedetomidine binds
      • α2A AR, KD 0.0014 uM
      • M3 mAChR, IC50 0.001 uM
    • Etomidate binds
      • α1β2γ2 GABAAR, EC50 1.08 uM
      • IK(dr), IC50 4.59 uM
      • α1 GlyR, IC50 5.37 uM
    • Midazolam binds
      • α1β2γ2 GABAAR, between the α1 and γ2 subunits, EC50 0.041 uM
      • NaV (neuron), IC50 0.074 uM
      • nAChR (muscle), IC50 0.143 uM
    • Diazepam binds α1β2γ2 GABAAR, EC50 0.07 uM
    • Sevoflurane binds Kv1.2, EC50 0.0097 mM
  • Some common anesthetics that are less selective, or not characterized in the paper
    • Propofol binds to α4β2 nAChR with IC50 of 3.13 uM, HCN1 receptors with IC50 of 4.19 uM, and α1β2γ2 with EC50 of 5.44 uM.
    • Remimazolam binds GABAA receptors non-selectively (i.e. αxβ2γ2)

Rx Probing Anesthetic-Receptor Interactions

  • Are there pharmacological agents with effects complementary to those of anesthetics with receptor specificity? Do they cross the blood brain barrier? Search ChEMBL.
Potential Anesthetic Antagonists
Receptor Anesthetic Antagonist Off-Target Effects? Crosses BBB Approved for Humans
α1β2γ2 GABAAR methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) Example Example Example
α1β2γ2 GABAAR Flumazenil (competitive inhibitor of benzodiazepine binding) protoporphyrin IX, α2,3,5, γ3 yes yes
α1β2γ2 GABAAR Diazepam (potentiates GABA's effects) ??? yes yes
HCN1 Example Example Example Example
α4β4 nAChR Example Example Example Example
GluN1/N2C NMDAR Example Example Example Example
α2A AR Example Example Example Example
M3 mAChR Example Example Example Example
Kv1.2 Example Example Example Example
  • When given at equipotent doses with propofol, how do diazepam's behavioral effects differ? How are they the same?
  • Would flumazenil block propofol's effect on the GABAAR, despite binding at a different site? What to make of the off-target effects?
  • When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABAAR inhibitor?

Genetic Probing of Anesthetic-Receptor Interactions

  • Are there genetic KO/KD or optogenetic tools available for location-specific inducible receptor knockdowns?
    • Optogenetics has been used to inhibit neurons (Boyden Zhang) and control motor responses in C. elegans (Nagel)
    • The effect of anion-conducting channelrhodopsins (ACRs) on the activity of the neuron is comparable to GABAA receptors.
    • Is the receptor, its components, or homologues of the gene expressed in different model organisms? What is the sequence similarity with human?
    • Search flybase, MGI, wormbase, zebra fish information network, yeast genome database
  • Where and by what cell types are these receptors expressed in the human brain?

Phylogenetic Approach

  • Are there organisms that are resistant to anesthetics? Search for 'weird' organisms that might yield something interesting. Prokaryotes (bacteria, archaea) and Eukaryotes (Protists, Plants, Animals, Fungi). Single cellular and Multicellular organisms. For resistant organisms, what is different about them?
    • Downsides of using 'weird' organisms is that there are relatively few genetic tools, antibodies, sparse literature, and few experts to consult.
    • Has anyone published behavioral assays for these organisms? How do you make an argument that a slime mold has been anesthetized?

Heterodox Hypothesis

  • If you can anesthetize single-celled organisms, are circuits irrelevant?
  • Hamilton has a gap junction (network of gap junctions?) and some specific neurons that he think are a conserved mechanism of anesthesia. He wants to test this by doing a screen of a bunch of different anesthetics in WT and KO worms with a behavioral screening assay. He has a behavior rig that basically automatically records swimming speed. He wants to look for the EC50 of various anesthetics and see if that number is shifted with KO or KD of different gap junctions.
  • Worms natively have a blue-light rhodopsin that triggers an aversion response where they turn around and go the opposite direction.
  • Next call 10/29.

CLAN

Alpha entrainment analgesia study

    • Successfully entrain alpha. What were we doing wrong? Is there anything in the literature that can guide a protocol modification?
    • Can I incorporate withdrawal thresholds?
    • Make it multi-center
    • Is alpha dropout selective for certain types of pain?
    • Power analysis based on pilot study
    • Systematic review and meta analysis
    • Simulation of inhibitory neurons in the ACC expressing channelrhodopsin-2 resulted in a reduction of reflexive acute pain responses in mice.

EEG nociceptive signatures

  • See Naloxone below for a start.
  • Increased delta power, decreased alpha power

EEG effects of anesthetic agents

Look at benzos, opioids, precedex, and their respective reversal agents. Also caffeine, methylphenidate, and methohexital. In MedLine, combine each agent with the search term Electroencephalography/ and add limits for Adults, Humans, and English. Which drugs are most target selective? What are their EEG effects?

  • Yohimbine = 9
    • 2005 paper shows that yohimbine stimulates NE release from the locus ceruleus.
    • 2002 article suggests that norepinephrine modulates CNS mechanisms of selective attention to infrequent stimuli (decreased latency of the P200 in ERPs).
    • 1994 paper reported speeding of N1 and single-trial P3 data indicate that noradrenergic drugs affect processing of early (visual) information. Yohimbine's speeding of P3 without changing RT is consistent with neural net (parallel) simulations but not with a serial model.
    • 1985 study showed yohimbine enhanced noradrenaline release, increased stage 1 and REM sleep, but decreased the stages 2 and 3 + 4; increases of mobility during REM and non-REM sleep signified desynchronization.
  • Naloxone = 28
    • 2021 study looking at 20 health male volunteers showed that the magnitude of nociceptive withdrawal reflexes (NWRs) together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated by opioids. In the cold-pressor test, increases in delta amplitude and decreases in alpha power were reversed by opioids.
    • 2010 study of 12 healthy volunteers demonstrated that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease.
    • Fentanyl self-administration and passive administration (both 1.5-3 mg/70 kg) have differential EEG effects. Delta EEG peak amplitude increases were greater following fentanyl SA than fentanyl PA, primarily over the central midline region, and were attenuated by naloxone pretreatment in a 2005 study of 8 heroin-dependent, methadone stabilized subjects.
    • EEG average frequency was increased in response to pain from direct 60 Hz thalamic electrical stimulation. The effect was blunted by fentanyl (5 mcg/kg) and augmented by naloxone (3.5 mcg/kg), in a 1998 study of 4 epileptic patients.
    • In a pain-evoked potential paradigm with patients undergoing minor surgical procedures, naloxone (3 mcg/kg) increased the amplitude and area of the small P300 while decreasing its latency, but decreased the amplitude and area of the large P300 peak. There were fewer omissions in an odd-ball task 1984 study of patients undergoing minor surgical procedures.
    • 1980 study of 16 patients failed to demonstrate a significant EEG response in response to 1.2 mg naloxone in patients under GA using inhalation (halothane ± N2O) anesthesia.
    • 1980 study showed painful electrical stimulation of the median nerve decreased SEP amplitude in six volunteers. In the four volunteers who noted that this pain-relief was inhibited by naloxone, the SEP amplitude was also returned to baseline following naloxone administration. Two volunteers had a paradoxical reaction.
    • 1979 study showed 10 or 20 mg of naloxone elicited a significant slowing of the average alpha frequency in healthy male volunteers
    • 1979 study reported that some of the analgesic effects of N2O can be reversed with naloxone 0.4 mg, as evidenced by electrical pain-evoked potentials.
  • Flumazenil = 94
  • Methylphenidate = 68
  • Methohexital = 80
  • Caffeine = 138

CO2

  • Does permissive hypercapnia improve hemodynamic stability, improve oxygen delivery to tissues, deepen anesthesia, and speed recovery?

Depression

  • Do ketamine, TIVA w/ propofol, TIVA w/ remimazolam, psychedelics, or burst suppression modulate the post-operative risk of depression?

Young Blood

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