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.
The gist
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.
Big reveals
- 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.
Things 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.
Recommended in this episode
Books, products and media the guest or host genuinely endorsed here — with the buy link.
Affiliate link — we may earn a commission at no extra cost to you.
BrainHQ
Posit Science
“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 01:29:53Find it on Amazon