The guest
Mark D'Esposito: Neurologist and professor of neuroscience and psychology at UC Berkeley, and a practicing clinician. He is a world expert in the brain mechanisms of executive function and working memory.
What this episode covers
Andrew Huberman interviews Dr. Mark D'Esposito about how the prefrontal cortex acts as the brain's executive 'conductor,' storing hierarchical rules and translating thought into goal-directed action. They explore working memory as the foundation of cognition and dopamine's role in sustaining it, including an inverted-U dose-response where more dopamine is not always better. The conversation covers pharmacological tools (bromocriptine, guanfacine) and why pharma has ignored cognitive enhancement, plus disease states including traumatic brain injury/concussion, Alzheimer's, and Parkinson's. They discuss optimizing brain health through sleep, aerobic exercise, mindfulness, reading, and cognitive training. D'Esposito closes with his excitement about brain-network 'modularity' as a predictive biomarker for who benefits from interventions.
Recommended on this episode
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BrainHQ
Posit Science
“I'd like to see more patients get started on some of those things; I think Mike's work has been um tremendous”
“now we talked about technology things like um brain HQ do you know about brain HQ so Mike merenik developed a company called posit science where developed these brain training games”— Mark D'Esposito
Also referenced (named, not recommended)
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Bromocriptine
“those who were that can only hold five or six letters if we gave them bromo crype which was the Doper nergic Agonist we improved their working memory”— Mark D'Esposito
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Guanfacine
“anything that um boosts norer nephrine can do it the one that we've used that's most used is guanfacine which is actually a blood pressure medication”— Mark D'Esposito
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Wellbutrin (bupropion)
“one is um Wellbutrin bronin uh I can never pronounce that um as far as I know it's a uh um epinephrine or norepinephrine Agonist”— Andrew Huberman
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Modafinil
“what about drugs like modafanil which are thought to be true cognitive enhancers um as opposed to um drugs that just kind of are designed to ramp up levels of alertness”— Andrew Huberman
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Sinemet (carbidopa-levodopa)
“it wasn't until we cinet came along which is has this debox decarbox inhib that blocks sort of the the the breakdown of doine that we were able to sort of get enough dopamine into the brain”— Mark D'Esposito
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Nicorette
Nicorette
“during the course of our one-hour meeting he consumed no fewer than four pieces of Nicorette gum and I said I got to ask what's this about”— Andrew Huberman
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Aricept (donepezil)
“the only approved uh treatment for Alzheimer's disease is a drug that boosts Asal Coline what's the drug right it's called deasil”— Mark D'Esposito
Big reveals from this episode
- Bromocriptine improves working memory only in people with low baseline dopamine; those already high are made worse, an inverted-U dose-response.
- Working memory capacity (how many letters/numbers you can hold) is a strong behavioral proxy for prefrontal dopamine levels.
- A COMT enzyme polymorphism, detectable by a simple saliva test, makes roughly 25% of people overactive and 25% underactive at clearing prefrontal dopamine.
- No pharmaceutical company has ever tried to develop a drug for improving cognition, despite the data and the established safety of existing compounds.
- Concussion is literally a tearing and stretching of axons, most commonly in the frontal lobes, and even a roughly 1% drop in performance has real-life impact.
- Aerobic exercise was found to be just as effective as dedicated cognitive therapy at improving executive function.
- Higher baseline brain-network 'modularity' (measured via fMRI) predicts who benefits most from cognitive training and other interventions.
- The frontal lobes are full of estrogen receptors; estrogen boosts dopamine, so working memory fluctuates with the menstrual cycle.
Worth remembering
- Insurance companies set car-rental age at 25 before neuroscientists knew the frontal lobes aren't fully developed until the early-to-mid 20s.
- Dr. Lhermitte's 1980s papers documented frontal-lobe patients who'd put on offered glasses, climb into a bed, or take blood pressure unprompted.
- Working memory and long-term memory are completely separate systems in different parts of the brain; one does not pass into the other.
- Prefrontal dopamine promotes stable representations while basal-ganglia dopamine enables updating, a stability-versus-flexibility balance.
- Bromocriptine was used by Olympic sprinters to shave reaction time off the blocks before it was added to the banned-substance list.
- A study at Penn found showing Alzheimer's patients family movies or albums helped behavior better than any drug.
- The only approved Alzheimer's drug class boosts acetylcholine but barely helps because acetylcholine isn't the primary deficit.
- A researcher could predict, before a sound played, whether a person in a scanner would detect it based on their moment-to-moment modularity.
- TMS to the prefrontal cortex can slow heart rate, showing the prefrontal cortex influences bodily organs through intermediate stations.
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