October 2026

Career Goals Over the long-term, I plan to explore the mechanisms whereby anesthetics lead to amnesia, hypnosis (impaired behavioral responsiveness), immobility, and analgesia. I aim to discover neural-activity correlates (e.g. EEG) specifically related to each of these and develop both pharmacologic and device-based methods to modulate them non-invasively. In the short-term, I am looking at describing EEG nociceptive and anti-nociceptive signatures and using neural entrainment to modulate pain-processing. Can TMS be used for spatially precise, steerable, low-latency cortical and sub-cortical stimulation and inhibition?

AY '26-'27 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.
- SCD-PV?
- 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). Ketamine may have an active metabolite that sticks around, explaining its long lasting 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

Research Connect on PULSE (Amy Monroe)
Lab meeting w/ Christian
Accepted invite to teach EEG workshop at February meeting (coordinate with Christian who does what)
IARS abstract submission deadline is 12/6 (methohexital, flumazenil/propofol patch clamp, SCD-PV)
Reach out to Grace about ketamine research brainstorm.
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 targets receptors (e.g. α4β2 nAChR, HCN1) are necessary or sufficient for its effects?
  - Assuming that α1β2γ2 GABA_AR is the critical receptor, can we demonstrate which circuits play a critical role?

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)

Patch clamp
Meeting with Hamilton

Lab meeting

IARS

SCD PV
Methohexital

Mechanisms of Anesthesia

Big picture: understand the temporospatial and molecular targets underlying neural activity changes 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?

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).
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? Detailed protocols for breeding them? Have they already been anesthetized?

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" GABA_AR 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
  - α_2A AR, K_D 0.0014 uM
  - M₃ mAChR, IC₅₀ 0.001 uM
- Etomidate binds
  - α1β2γ2 GABA_AR, EC₅₀ 1.08 uM
  - I_K(dr), IC₅₀ 4.59 uM
  - α1 GlyR, IC₅₀ 5.37 uM
- Midazolam binds
  - α1β2γ2 GABA_AR, between the α1 and γ2 subunits, EC₅₀ 0.041 uM
  - Na_V (neuron), IC₅₀ 0.074 uM
  - nAChR (muscle), IC₅₀ 0.143 uM
- Diazepam binds α1β2γ2 GABA_AR, EC₅₀ 0.07 uM
- Sevoflurane binds K_v1.2, 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 GABA_A 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 GABA_AR	methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)	Example	Example	Example
α1β2γ2 GABA_AR	Flumazenil (competitive inhibitor of benzodiazepine binding)	protoporphyrin IX, α2,3,5, γ3	yes	yes
α1β2γ2 GABA_AR	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
α_2A AR	Example	Example	Example	Example
M₃ mAChR	Example	Example	Example	Example
K_v1.2	Example	Example	Example	Example

When given at equipotent doses with propofol, how does Diazepam's behavioral effects differ? How are they the same?
Would flumazenil block propofol's effect on the GABA_AR, 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_AR 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?

Non-Receptor Mediated Hypothesis

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 10/14.

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?