How to Optimize Cognitive Function & Brain Health | Dr. Mark D'Esposito

KEYPOINTS

• 01

  The prefrontal cortex is the brain's CEO, and it's the first system to falter

  D'Esposito, a neurologist, defines executive function or 'cognitive control' as the ability to plan, organize and turn goals into actions rather than being ruled by automatic behavior. The frontal lobe has perhaps 25 subregions, with the lateral portion central to executive function. Sleep deprivation, stress and normal aging hit this system first, which is why everything feels harder on a bad day. He notes that insurers' age-25 cutoff roughly tracks when frontal lobes finish maturing.

• 02

  Working memory is active manipulation, not passive storage

  Working memory is holding information in mind while doing something with it, like a math problem or planning a sentence, and it's the foundation of executive function. Neurons in the frontal lobes keep firing persistently while information is held. D'Esposito explains that dopamine acts as a modulator that keeps this persistent activity stable. Deplete dopamine and working memory drops significantly, and replace it and performance recovers.

• 03

  Dopamine and working memory follow an inverted U

  In D'Esposito's studies, people with a low working-memory span (holding about five or six letters) improved on bromocriptine, a dopamine agonist, while people with a high span got worse. PET scans showed span correlates strongly with frontal dopamine, so a simple span task can serve as a rough behavioral proxy for baseline dopamine. 'More is just not better,' he says. The goal is to bring people to their optimal level.

• 04

  Genetics sets your dopamine baseline

  The enzyme COMT breaks down dopamine in the prefrontal cortex. D'Esposito estimates that in roughly 25% of people it's overactive and in another 25% underactive, though this varies by ancestry, so about half the population sits off-center. Knowing your COMT status and span may eventually help predict who benefits from boosting dopamine and who would be harmed.

• 05

  Healthy volunteers can't tell when bromocriptine is helping

  Bromocriptine is short-acting (about four to six hours) and kicks in roughly 90 minutes after dosing. D'Esposito says healthy subjects on low doses can't distinguish it from placebo and don't feel 'buzzed.' They only learn their working memory improved when shown the data, and the gains reflect better performance, not just speed. He's disappointed that drug companies, focused on disease markets, never took up cognitive optimization with these already-approved drugs. Huberman stresses he is not encouraging anyone to take it.

• 06

  Norepinephrine is another lever, and combinations may matter

  Anything that boosts norepinephrine seems to help executive function. Guanfacine, a blood-pressure drug, is the most used, and D'Esposito says a study found it improved COVID brain fog, with trials now under way. Neuromodulators interact: in one example, low doses of two drugs were effective together when neither worked alone. On stimulants like Adderall, Vyvanse and Ritalin, he says decisions belong with a psychiatrist, and he cites the 1980s Wall Street cocaine culture as proof that 'more is better' fails.

• 07

  Concussion recovery: protect sleep, move as tolerated, retrain skills

  Almost every concussion patient reports poor sleep, which compounds deficits, and a large share still feel mentally foggy, light-sensitive or dizzy a year out. Advice has shifted from dark-room rest to activity as tolerated without worsening headache or light sensitivity. Patients who feel fine after a couple of weeks off often find their first day back at work a disaster, so D'Esposito favors a graded return. Goal management training helps but isn't covered by insurance, so '99%' of his patients get no intervention. He points to online training like BrainHQ as a scalable option.

• 08

  Estrogen modulates frontal dopamine

  The frontal lobes may hold more estrogen receptors than any other brain region, and estrogen boosts dopamine. In a study by a colleague, Berkeley undergraduates were tested at low- and high-estrogen points of the menstrual cycle and genotyped for COMT. Frontal function and working memory dipped at low estrogen, especially in those with low baseline dopamine. This fits anecdotal reports of working-memory gains in postmenopausal women on estrogen.

• 09

  Aerobic exercise and mindfulness train executive function directly

  Arthur Kramer's group at the University of Illinois found aerobic exercise as effective as cognitive therapy for improving executive function. D'Esposito frames mindfulness (focusing on the breath, noticing when focus drifts and returning) as focus training, since losing focus is 'half the problem' with not reaching goals. In his studies, the specific style didn't seem to matter.