Big List of Neuromodulation Modalities

Every way to change your mind.

Please make an issue if something's missing!

Table of Contents

• Cognitive (requiring conscious engagement)
• Peripheral (entering the brain via nerves from outside the skull)
• Biologic
• Chemical (small molecules)
• Subatomic
• Electromagnetic
• Mechanical
• Combination

Cognitive

• meditation
  • concentrative
    • focusing on a specific sensation or thought, like the breath
    • metta
    • gratitude practices
  • open monitoring
• psychotherapy
  • cognitive behavioral therapy
• neurofeedback
• hypnosis
• breathwork
• brain training
  • Akili Interactive targeting ADHD
  • action video games to reduce depression
• conditioning
  • disulfiram
• social engagement
  • friendships
  • romance
  • group activities (games, sports, dance)

Peripheral

• activities
  • walking
  • exercise
  • eating
  • breathing techniques
  • sauna
  • cold plunge
• sensory stimuation
  • music
  • binaural beats
  • auditory entrainment, e.g. Elemind
  • audiovisual entrainment, e.g. Cognito (currently in Breakthrough Designation Phase 3 for Alzheimer's)
  • vibrotactile stimulation
• sensory deprivation
• peripheral nerve stimulation
  • vagus nerve stimulation (FDA-approved for depression, epilepsy)
  • trigeminal nerve stimulation
  • auricular nerve stimulation
  • percutaneous nerve field stimulation
  • cochlear implants
  • auditory brainstem implant (technically not peripheral, but right on the border)
  • retinal implants
  • science.xyz

Biologic

These are currently uncommon due to the difficulty of getting biologics across the blood-brain barrier, but there are many in the pipeline. Interesting targets include FAAH-OUT and rs324420 for potential pain insensitivity and short-sleeper genes.

• antibodies
  • CGRP antagonists for migraine exist but act on peripheral nerves
  • endogenous antibodies
    • anti-ganglioside antibodies
    • anti-glutamate receptor antibodies
    • voltage-gated potassium channels antibodies
• proteins and peptides
  • Peptides for stroke. Guess that's one way around the BBB...
  • Peptides for Alzheimer's. Unknown how they cross the BBB.
• nucleic acids
  • in-vivo AAV gene therapy to increase BDNF
  • antisense oligonucleotides
• live cells
  • cell therapy for depression and potentially other things
  • ex-vivo modified autologous fibroblasts to produce nerve growth factor

Chemical

There are too many chemicals to list, so instead here are the key mechanisms and effects by which we categorize chemicals, followed by some examples.

Mechanisms of action of psychoactive substances

This is a mostly comprehensive list. Most chemicals act by multiple mechanisms.

• receptor modulation
  • agonism (activates a receptor on a cell)
    • It's actually more complicated due to biased agonism
  • antagonism (binds to but doesn't activate a receptor, a "blocker")
  • inverse agonism (binds a receptor but produces an opposite effect)
  • allosteric modulation (binds somewhere other than the active site and increases/decreases activity)
• enzyme modulation
  • induction
  • inhibition
• ion channel modulation
  • opening
  • blocking
• transporter modulation
  • neurotransmitter release enhancement
  • neurotransmitter release inhibition
  • reuptake enhancement
  • reuptake inhibition

Neurological and psychological effects of psychoactive substances

This is definitely not a comprehensive list, just commonly used terminology.

• depressants
  • anxiolytics/sedatives (reduce anxiety)
  • hypnotics (make you sleep)
• hallucinogens (alter perception)
  • psychedelics
  • dissociatives
  • anesthetics
  • deliriants
  • empathogens/entactogens (emotional openness, empathy, sympathy)
• stimulants (may cause euphoria, but do not affect perception)
• mood stabilizers
• antidepressants
• antipsychotics

Examples

• caffeine: stimulant; adenosine receptor antagonist (among other things)
• fluoxetine (prozac): antidepressant; selective serotonin reuptake inhibitor (SSRI)
• haloperidol: antipsychotic; dopamine receptor antagonist
• clozapine: antipsychotic; 5-HT2A antagonist
• cocaine: stimulant; serotonin, norepinephrine, and dopamine reuptake inhibitor
• nicotine: stimulant and anxiolytic; nicotinic acetylcholine receptor agonist/antagonist
• phenethylamines
  • substituted amphetamines
    • amphetamine (adderall): stimulant; TAAR1 agonist (among other things)
    • MDMA: stimulant and empathogen; serotonin, norepinephrine, and dopamine reuptake inhibitor
  • mescaline: psychedelic; 5-HT2A agonist
• tryptamines
  • psilocybin: psychedelic; 5-HT2A agonist
  • N,N-Dimethyltryptamine (DMT): psychedelic, nonselective 5HT and dopamine (ant)agonist
  • melatonin: hypnotic; melatonin receptor agonist
• arylcyclohexylamines
  • ketamine: dissociative anesthetic; NMDA receptor antagonist
  • phencyclidine (PCP): dissociative anesthetic; NMDA receptor antagonist
• elements
  • Lithium: mood stabilizer, multifarious enzyme modulator
  • Xenon: dissociative anaesthetic, unknown mechanism
• nitrous oxide: dissociative anesthetic; ion channel blocker (among other things)
• morphine: anesthetic; opioid receptor agonist
• benzodiazepines
  • diezepam (valium): anxiolytic and hypnotic; positive allosteric GABA-A receptor modulator
  • alprazolam (xanax): anxiolytic; positive allosteric GABA-A receptor modulator
• valproate: mood stabilizer, anticonvulsant; voltage-gated sodium channel blocker, histone deacetylase (HDAC) inhibitor (nice notes on HDAC inhibitors here)

Subatomic

• electronic
  • electron beam therapy
  • beta-decay radiotherapy
• hadronic
  • proton therapy
  • fast neutron therapy
  • heavy-ion radiotherapy

Electromagnetic

• electroconvulsive therapy (ECT) (undeserved bad reputation, safe and often effective for depression when done under general anesthesia)
• microelectrode stimulation
  • deep brain stimulation (DBS)
  • cortical stimulation (RNS Therapy, Nia Therapeutics, etc.)
  • intracortical arrays (braingate, paradromics, neuralink, etc.)
  • stent-mounted array (stendrode)
• transcranial electrical stimulation (tES) (running currents through the brain)
  • transcranial direct current stimulation (tDCS) (less effective than popularly portrayed, but useful for specific indications)
  • transcranial random noise stimulation (tRNS)
  • transcranial alternating current stimulation (tACS)
  • temporal interference
• induction with magnetic fields
  • transcranial magnetic stimulation (TMS)
    • FDA-approved for depression, migraines, OCD, and smoking cessation
  • low field magnetic stimulation
    • Company blew their clinical trial, but that was probably due to rushing the trial and not inefficacy
• photonic
  • photobiomodulation/low-level light therapy
    • Big review of light penetrance in the brain
  • x-ray
  • gamma knife
  • gamma-decay radiotherapy

Mechanical

• invasive surgery
  • lobotomy
  • corpus callosotomy
  • invasive thalamotomy
  • many other -tomys
• ultrasound
  • high-intensity focused ultrasound (HIFU) (for ablation)
  • blood-brain barrier opening
  • transcranial focused ultrasound stimulation (TUS) (direct neural activity modulation by low-intensity ultrasound)

Combination

• environmental
  • nutrition
  • genetic makeup
  • social life
  • prenatal environment
  • gut-brain axis/microbiome
• optogenetics
  • and optogenetic cell therapy
• chemogenetics
• sonogenetics
• sonothermogenetics
• sonomagnetics
• antibody-drug conjugates
• ultrasound blood-brain barrier opening for drug delivery

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