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The frontal lobes: the Brain’s CEO

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Mark D’Esposito discusses the mechanisms critical for working memory, the architecture of the lateral Prefrontal cortex and how neurochemical systems modulate the PFC.

Image courtesy of interviewee. April 4, 2024

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This video video discusses the concept of working memory and its critical role in cognitive functioning. Working memory is defined as the temporary retention and manipulation of information that is no longer present in the environment, such as recalling a phone number or social security number. It is crucial for tasks like reading comprehension and reasoning and is closely linked to academic performance.

The prefrontal cortex, particularly the portion in front of the motor cortex, is identified as the key brain region responsible for working memory. This video video area is involved in both holding information and organizing it hierarchically—from concrete details to abstract concepts like goals. Damage to the prefrontal cortex can lead to significant impairments in working memory.

The neurochemical dopamine plays a significant role in the functioning of the prefrontal cortex. Research shows that dopamine levels impact working memory performance, with depletion leading to deficits. Other neuromodulators like acetylcholine also affect memory processes differently.

The importance of executive function is emphasized: it encompasses the abilities to plan, organize, and control behavior. Dysfunction in these areas can result in inappropriate or impulsive actions. This video video notes cognitive therapies developed to address deficits in executive function, helping individuals, including those with frontal lobe injuries, improve their organizational skills and overall cognitive function. Such therapies may also benefit healthy individuals by enhancing their executive functioning in daily life.

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Well, working memory refers to this temporary retention

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of information that we've just experienced,

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but no longer exist in the environment.

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So when someone tells you a cell number

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to enter into your phone,

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you rely on your working memory.

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Or it might even be information

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that you're retrieving from your own brain, such as,

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you know, remembering your social security number

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or a number if you've gotta put down in, in a tax form.

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So the, these type of, representations

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or memories in the brain are short-lived.

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Uh, but you can store them for longer periods of time for

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as long as you, you know, as long as you rehearse 'em.

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Um, but the important part

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of working memory is the working part.

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Um, it's, it's, we hold information in mind,

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but we can also manipulate that information in ways

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that's useful for us.

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We can perform calculations in our head.

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Um, we can keep a mind, you know,

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someone's face in mind when we're searching

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for them in a crowded room.

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So working memories a really critical function in cognition.

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Uh, it's important for many cognitive abilities, such

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as reasoning and reading comprehension.

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Uh, if you read a book

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or you're trying to understand a conversation,

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obviously you have to hold, that sentence in mind,

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or hold that, you know, whether it's reading or hearing.

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And so, and it turns out our working merit capacity is very

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predictive about how well we can read, how well we write,

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how well we follow directions,

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how well we achieve, in school.

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So it's a critical sort of founding building block

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for all of cognition.

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It was discovered that the part of the brain

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that seems most important

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for working memory is the frontal lobes,

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and specifically the prefrontal cortex.

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The frontal lobes are complicated

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and made up of many sub regions,

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but there's a portion in front of

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the motor cortex called the prefrontal cortex.

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And it was discovered that there were neuro brain cells

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within the prefrontal cortex that are active.

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When someone is holding, information in mind,

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there is this persistent neural activity,

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that exists in these cells.

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And so the prefrontal cortex is the part of the brain

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that's most critical working memory.

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And if you damage the prefrontal cortex,

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you have an impairment, in working memory.

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What we've learned really is that, not only it's,

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it's important for holding information

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anywhere in the brain.

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So when you're holding up a face

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or holding up a telephone number, that, you know,

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those parts of the brain, the prefrontal cortex kind

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of calls up those parts of the brain.

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It, it turns out that the brain doesn't really have these

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buffers where you're sending information in like ram

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of a computer, but the prefrontal cortex does, it just

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activates the other parts of the brain.

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So if you're trying to hold up a fa yeah,

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hold onto a face in mind, it will sort of activate

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that part of the face ar the face part of the brain in,

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in order to keep that information up.

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And so the prefrontal cortex to acts as, as kind of

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as a controller controlling the rest of the brain.

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Um, but it does also store information.

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The prefrontal cortex seems

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to store the most important information we have,

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and that's our rules.

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Uh, it that's our goals. Uh, that's our intentions.

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And that's why, we think of the prefrontal cortex

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as this very important, controller

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or the CEO of the brain

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or the conductor, you know, of, of the orchestra.

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The prefrontal cortex is in this very

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pro privileged position.

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It projects almost to every other part of the brain,

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both within the cerebral cortex

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and within the subcortical regions, such

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as the basal gang hypothalamus

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and almost every other region of the brain projects to it.

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So it's, it's, again, this metaphor of the CEO is, is,

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is a good one because it really has,

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its sites on everything

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and everything can, can direct back to it.

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Um, so it it, it's organized in a way

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that it can influence other parts of the brain

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and the information that's coming in will influence it.

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But within the prefrontal cortex, it's been very interesting

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that it has its own organization,

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and it's organized in a very unique way,

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what we call hierarch hierarchical, meaning that

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there are lower and higher areas.

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And so even within this CEO of the brain, there,

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there is areas that are higher up in the hierarchy

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and areas that are lower up in the hierarchy.

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And as we've studied it, if you, look at the anatomy

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of the prefrontal coordinators as you go from the back

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of the prefrontal cor to the front, the type of information

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that it stores gets more abstract.

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So when you're, when you're closer to the back

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of the prefrontal cortex, the type

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of information is more concrete.

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It might be a very, it might be just the information

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that you need to, to, to act.

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Um, whereas as you move up the hierarchy,

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it could be a very abstract representation,

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such as, such as a goal.

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Um, so I can give you an example.

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So for example, and we store all different levels

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of representations all the time,

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and we're, when we're doing whatever we're doing,

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we don't just hold one piece of information on mind.

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So for example, I like to give the example of, of golfing.

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If you're, if you're golfing

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and you happen to find yourself, off the fairway in a,

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in a bush, an unfortunate situation,

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there's many different types of information

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that you're holding in mind in order to achieve the goal

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of getting your golf ball back onto the, onto the fairway.

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So the lowest level might just be a memory of

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where the green is, where you have to aim,

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and that's a very concrete kind of representation.

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But you're also holding other information.

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You're in a bush, you have to hold onto what the rules are,

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you know that you can't kick the ball out of the,

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the bush because you'll have a penalty.

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So you, you maintain that representation in order

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to hit the golf ball.

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And then you might even hold a very abstract representation

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like, why am I doing this?

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Because I was out here just to have exercise

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and lower my blood pressure and enjoy, enjoy things.

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So all of these different abstracts, levels

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of representations are stored in the prefrontal cortex,

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but they're organized hierarchically, which allows us

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to kind of parallel process

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and keep all of this information together in the same time

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in order to, sort of translate

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our knowledge into some type of action.

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You can push it out as

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Far, I think, as far as humanly possible.

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I think the highest, the highest level of abstraction is,

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is a meta, is a meta, what we call metacognition.

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That there is, it's, it's very abstract in, in terms

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of even, even more abstract than the goal of, of health

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and, and, and wellbeing.

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And, and yeah, I think that's something that,

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the prefrontal cortex, you know,

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the prefrontal cortex takes it as high as,

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as humans can, can abstract.

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Um, but, but, but all of that is,

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and those abstracts go very abstract goals,

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will influence your actions just as much as the very

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concrete, representations that you store.

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So, like I said, the prefrontal cortex is communicating

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with the rest of the brain,

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and the rest of the brain is communicating with it.

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So we're, we're constantly bombarded with information,

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and we have to choose what we're gonna pay attention to

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and what we're gonna act on

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and what we're not when we're driving home.

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And our goal is to stop off and get, you know, some milk.

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We have to, we have to keep that representation intact

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and not be distracted by maybe going off and,

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and doing something else.

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Uh, so there's been a number of studies that show

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that the prefrontal cortex is the source of that,

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the signaling.

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So for example, we've done experiments where,

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just on the computer

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or behavioral experiments where you're,

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where you see information come, you have to ask, you have

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to remember faces or scenes.

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Um, but on some trials we say, we want you

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to remember the faces, and we want you to ignore the scenes

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and others, we want you

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to remember the scenes ignore the faces,

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but you're being presented with faces and scenes.

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And so if it was just a bottom up system

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where you're just drawn by everything that comes in,

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you would just store everything.

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Um, but what the prefrontal cortex is, is directs you,

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directs, the brain towards processing the faces when

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that's relevant and processing the scenes when

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that that's relevant.

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It can so efficiently allows you to control,

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your behavior based on what the rule is

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or based on what the instructions are, based on

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what your, your goal is.

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So again, it's kind of the CEO, it's the conductor that's,

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of kind of organizing

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how information's being processed through the brain.

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So there are a number of neural chemicals

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that are synthesized in the brainstem.

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Uh, we call these the brainstem modulatory systems.

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There's acetylcholine, there's dopamine,

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there's norepinephrine,

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and all of these, all

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of these neurochemicals influence the cortex

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by way they project to the brain.

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So each of these modulatory systems project

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to different parts of the brain.

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And by the way, they project, that's

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how they influence the brain.

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So when you look at the dopaminergic neurons in the brain,

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there's more projections

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to the prefrontal cortex than any other part of the brain.

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So dopamine seems to be something

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specifically acting on the, on the prefrontal cortex.

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And there's more of these, there's more dopamine receptors

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in the prefrontal cortex.

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So it was discovered quite a long time ago

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that if you deplete dopamine in the brain,

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you will impair working memory

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and you'll impair frontal lobe function.

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Or if you enhance, dopamine, you'll improve,

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working memory or frontal lobe function.

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And other transmitters have other functions.

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So for example, acetylcholine acts on the hippocampus and,

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and boosting acetylcholine will improve a different type

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of memory, which is called long-term memory.

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So dopamine and working memory

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and functions are intimately tied.

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What's interesting about dopamine is it also projects

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to the basal ganglia.

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And so we know a lot about it

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because in Parkinson's disease, there's a depletion

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of dopamine in the striatum, in the basal ganglia,

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and that leads to all of the motor,

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findings that we see.

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But when you deplete it in the prefrontal cortex,

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you have these cognitive, deficits.

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And there's this rare, very interesting balance

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between the prefrontal cortex

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and the, basal ganglia in terms

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of its domineer function.

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It's thought that the, that the, basal ganglia allows us

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to update our working memory.

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So when we're holding something in mind,

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but we have new information, we have to update it.

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And, the dopa neurotic input into the basal ganglia

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seems to allow that updating process to happen.

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Whereas in the prefrontal cortex, what's very important is

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to hold that information in mind and keep it stable.

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Don't let it, don't let it disappear.

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And the pref and the dopaminergic input into the prefrontal

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cortex allows that stability.

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So in that way, dopamine allows for the dopamine

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and the basal ganglia allows for the flexibility

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that we have in our frontal lo function

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and the, in our working mem, sorry.

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And then the, the dour input into the prefrontal corus

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allows that cognitive stability that we have so

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that we're able to not be rigid and,

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and not to be dis distracted.

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Yeah. So what's very interesting is, is,

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hormones is a little bit late to the game in terms

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of frontal lobe function.

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There's, first was the study of dopamine

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and later came hormones.

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There's actually quite a lot of work on the effect of,

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estrogen on frontal low function.

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It turns out that there's estrogen receptors all throughout

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the brain, and there's more estrogen receptors within the

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prefrontal cortex than any other part of the brain.

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And it was discovered that if you,

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that dopamine will increase estrogen activity

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and increase the estro, I'm sorry, estrogen will increase,

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dopamine activity

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and increase the synthesis of dopamine.

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So the estrogen that's being produced

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by the pituitary is in turn, modulating,

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dopamine.

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And so another, you know, observation is

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that in postmenopausal women with low estrogen,

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there is working memory difficulties that can be improved

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with estrogen treatment.

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And we've done a number of studies.

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Uh, Emily Jacobs, when she was a graduate of my lab,

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did a study where she looked at women at different stages

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of their estrogen cycle and measured their dopamine function

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and measured their frontal, lo functional FMRI,

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and showed that when their,

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their estrogen was the lowest, their

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Dopamine was the lowest, and their frontal

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lobe function was the lowest.

11:56.265 --> 12:00.245
So hormones become incredibly another important modulator

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of frontal lobe function in addition to, dopamine,

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really, I'm a practicing neurologist

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and I see patients all the time of frontal lobe injury.

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And I can see the link between these basic mechanisms

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and what they're, what they show at the bedside

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or in, in the real world.

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Um, that wasn't true 30 years ago.

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It was very perplexing to me, the real life behaviors,

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trying to link it back.

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But we've have so much, we've gained

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so much knowledge over the last 30 years

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that mechanisms such as working memory impairments

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or inability to maintain a, a goal or abil

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or our ability to sort of switch

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and prioritize you, you can see how that plays out, how

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that plays out in the real world.

12:41.865 --> 12:45.125
So for e example, there's a behavior called imitation

12:45.125 --> 12:47.845
and utilization behavior that these patients can have.

12:48.625 --> 12:49.845
Uh, Dr. Lait,

12:49.985 --> 12:53.405
his neurologist in France showed back in the eighties,

12:53.405 --> 12:55.245
this behavior very nicely.

12:55.865 --> 12:57.925
For example, one, he sat in front of a patient

12:57.925 --> 12:59.045
with frontal lobe damage

12:59.545 --> 13:02.245
and he put a pair of glasses on the table,

13:02.245 --> 13:04.485
and he didn't instruct the patient to do anything

13:04.755 --> 13:08.045
with those glasses, and the patient just picked them up

13:08.105 --> 13:10.085
and put them on, even though he had a pair

13:10.085 --> 13:11.365
of glasses on already.

13:11.465 --> 13:13.245
So it wasn't the appropriate context,

13:13.385 --> 13:14.925
and he wasn't instructed to do so.

13:15.225 --> 13:16.525
And it was even embarrassing.

13:16.945 --> 13:18.765
He even brought this patient to his home,

13:19.385 --> 13:20.565
just to see what he'd do.

13:20.565 --> 13:22.085
And the patient was just walking around.

13:22.225 --> 13:24.565
And when he walked into the bedroom, he saw Dr.

13:24.915 --> 13:27.325
LA's bed and he just pulled, took off his clothes,

13:27.325 --> 13:29.165
pulled off the covers, and jumped in bed.

13:29.705 --> 13:33.045
And again, it wasn't the appropriate court, context.

13:33.705 --> 13:35.725
We know that where if we're in someone's office

13:35.865 --> 13:38.765
or doctor's office and the doctor's out leaves

13:38.825 --> 13:40.605
and the phone rings, we don't pick up the phone.

13:40.865 --> 13:42.845
If it was our office, we'd pick up the phone.

13:42.905 --> 13:47.005
So it's the frontal cortex that maintains the proper,

13:47.005 --> 13:49.485
context for how we behave,

13:49.665 --> 13:51.565
and it allows us to sort of translate

13:51.565 --> 13:54.525
that knowledge into the appropriate act action.

13:54.585 --> 13:57.085
And so without that frontal lobe control,

13:57.505 --> 14:00.965
we observe these type of, unusual, behaviors in,

14:00.965 --> 14:03.565
in our patients that are not socially appropriate.

14:03.945 --> 14:05.245
So the, these kind of behaviors,

14:05.305 --> 14:06.965
I'm talking about this in parent, we,

14:06.985 --> 14:09.525
we call it these executive function deficits

14:09.545 --> 14:12.005
or cognitive control deficits when you have damage

14:12.025 --> 14:14.565
to the frontal lobes, these, these are all of the abilities

14:15.035 --> 14:17.525
that allow us to guide our behavior based on goals

14:17.525 --> 14:20.765
and intentions, rather than just be automatically driven

14:20.865 --> 14:22.045
by what's around us.

14:22.625 --> 14:26.165
So this ability, if to organize, to plan,

14:26.665 --> 14:30.365
to set priorities, to monitor our behavior that's flexible

14:30.365 --> 14:34.005
and adaptable, this can all be translated into very

14:34.005 --> 14:36.685
sophisticated cognitive therapies that can be helpful.

14:37.185 --> 14:39.445
So the real breakthrough in my mind is

14:39.445 --> 14:42.605
that the cognitive therapies that have been developed,

14:42.605 --> 14:45.125
really were based on these fundamental mechanisms

14:45.125 --> 14:46.365
of prefrontal function.

14:46.875 --> 14:48.285
They weren't,

14:48.295 --> 14:50.845
based on just the phenomenology of what we saw.

14:51.465 --> 14:52.805
Now they're based on this is

14:52.805 --> 14:54.885
what we think the prefrontal cortex does,

14:54.985 --> 14:56.005
as I've just explained.

14:56.005 --> 14:57.565
And now we're gonna develop therapies

14:57.565 --> 14:59.845
that target those mechanisms.

14:59.865 --> 15:01.005
So for example, one

15:01.005 --> 15:03.485
of 'em is called goal management training,

15:03.485 --> 15:05.165
which was developed by Ian Robertson

15:05.705 --> 15:08.925
and Brian Levine at the University of Toronto, specifically

15:09.655 --> 15:13.445
aimed at sort of, you know, teaching strategies,

15:13.705 --> 15:18.085
to learn how to organize and to plan and to set priorities

15:18.105 --> 15:19.565
and to monitor your behavior.

15:20.025 --> 15:21.765
And so you can learn these strategies

15:21.905 --> 15:25.325
by doing progressively more complex tasks over time.

15:25.945 --> 15:28.445
You start with individual projects such

15:28.445 --> 15:31.685
as planning a mail meal or planning a family reunion.

15:32.265 --> 15:34.605
Uh, and then you sort of work your way up to sort

15:34.605 --> 15:36.045
of more complex tasks.

15:36.145 --> 15:38.965
And after doing these therapies, our patients

15:38.965 --> 15:42.765
with frontal injury feel significantly, better

15:42.825 --> 15:45.045
and do better on executive function tasks.

15:45.065 --> 15:49.325
And as you can imagine, we all are not optimized sometimes

15:49.355 --> 15:50.605
with our executive function.

15:50.625 --> 15:52.445
So this can help us, us, us all.

15:52.465 --> 15:55.085
So even when we've done this therapy on healthy elderly,

15:55.275 --> 15:58.245
they feel better, they feel they get things done better,

15:58.315 --> 15:59.565
they feel more organized.

15:59.565 --> 16:00.885
And so I feel it's definitely something

16:01.015 --> 16:02.365
we've talked about disease a lot.

16:02.365 --> 16:05.925
I think it's also something that can really be embedded into

16:05.995 --> 16:07.845
what we do, you know, in school

16:07.945 --> 16:09.325
or what we do in our real life

16:09.345 --> 16:11.085
or what we do, in the workplace.

00:00 - Well, working memory refers to this temporary retention of information that we've just experienced, but no longer exist in the environment. So when someone tells you a cell number to enter into your phone, you rely on your working memory.

00:12 - Or it might even be information that you're retrieving from your own brain, such as, you know, remembering your social security number or a number if you've gotta put down in, in a tax form. So the, these type of, representations or memories in the brain are short-lived. but you can store them for longer periods of time for as long as you, you know, as long as you rehearse 'em. but the important part of working memory is the working part.

00:35 - it's, it's, we hold information in mind, but we can also manipulate that information in ways that's useful for us. We can perform calculations in our head. we can keep a mind, you know, someone's face in mind when we're searching for them in a crowded room. So working memories a really critical function in cognition. it's important for many cognitive abilities, such as reasoning and reading comprehension.

00:58 - if you read a book or you're trying to understand a conversation, obviously you have to hold, that sentence in mind, or hold that, you know, whether it's reading or hearing. And so, and it turns out our working merit capacity is very predictive about how well we can read, how well we write, how well we follow directions, how well we achieve, in school. So it's a critical sort of founding building block for all of cognition.

01:23 - It was discovered that the part of the brain that seems most important for working memory is the frontal lobes, and specifically the prefrontal cortex. The frontal lobes are complicated and made up of many sub regions, but there's a portion in front of the motor cortex called the prefrontal cortex. And it was discovered that there were neuro brain cells within the prefrontal cortex that are active.

01:45 - When someone is holding, information in mind, there is this persistent neural activity, that exists in these cells. And so the prefrontal cortex is the part of the brain that's most critical working memory. And if you damage the prefrontal cortex, you have an impairment, in working memory. What we've learned really is that, not only it's, it's important for holding information anywhere in the brain.

02:12 - So when you're holding up a face or holding up a telephone number, that, you know, those parts of the brain, the prefrontal cortex kind of calls up those parts of the brain. It, it turns out that the brain doesn't really have these buffers where you're sending information in like ram of a computer, but the prefrontal cortex does, it just activates the other parts of the brain. So if you're trying to hold up a fa yeah, hold onto a face in mind, it will sort of activate

02:36 - that part of the face ar the face part of the brain in, in order to keep that information up. And so the prefrontal cortex to acts as, as kind of as a controller controlling the rest of the brain. but it does also store information. The prefrontal cortex seems to store the most important information we have, and that's our rules. it that's our goals. that's our intentions. And that's why, we think of the prefrontal cortex

03:00 - as this very important, controller or the CEO of the brain or the conductor, you know, of, of the orchestra. The prefrontal cortex is in this very pro privileged position. It projects almost to every other part of the brain, both within the cerebral cortex and within the subcortical regions, such as the basal gang hypothalamus and almost every other region of the brain projects to it.

03:22 - So it's, it's, again, this metaphor of the CEO is, is, is a good one because it really has, its sites on everything and everything can, can direct back to it. so it it, it's organized in a way that it can influence other parts of the brain and the information that's coming in will influence it. But within the prefrontal cortex, it's been very interesting that it has its own organization, and it's organized in a very unique way,

03:51 - what we call hierarch hierarchical, meaning that there are lower and higher areas. And so even within this CEO of the brain, there, there is areas that are higher up in the hierarchy and areas that are lower up in the hierarchy. And as we've studied it, if you, look at the anatomy of the prefrontal coordinators as you go from the back of the prefrontal cor to the front, the type of information that it stores gets more abstract. So when you're, when you're closer to the back

04:20 - of the prefrontal cortex, the type of information is more concrete. It might be a very, it might be just the information that you need to, to, to act. whereas as you move up the hierarchy, it could be a very abstract representation, such as, such as a goal. so I can give you an example. So for example, and we store all different levels of representations all the time,

04:42 - and we're, when we're doing whatever we're doing, we don't just hold one piece of information on mind. So for example, I like to give the example of, of golfing. If you're, if you're golfing and you happen to find yourself, off the fairway in a, in a bush, an unfortunate situation, there's many different types of information that you're holding in mind in order to achieve the goal of getting your golf ball back onto the, onto the fairway. So the lowest level might just be a memory of

05:09 - where the green is, where you have to aim, and that's a very concrete kind of representation. But you're also holding other information. You're in a bush, you have to hold onto what the rules are, you know that you can't kick the ball out of the, the bush because you'll have a penalty. So you, you maintain that representation in order to hit the golf ball. And then you might even hold a very abstract representation like, why am I doing this?

05:33 - Because I was out here just to have exercise and lower my blood pressure and enjoy, enjoy things. So all of these different abstracts, levels of representations are stored in the prefrontal cortex, but they're organized hierarchically, which allows us to kind of parallel process and keep all of this information together in the same time in order to, sort of translate our knowledge into some type of action. You can push it out as

05:56 - Far, I think, as far as humanly possible. I think the highest, the highest level of abstraction is, is a meta, is a meta, what we call metacognition. That there is, it's, it's very abstract in, in terms of even, even more abstract than the goal of, of health and, and, and wellbeing. And, and yeah, I think that's something that, the prefrontal cortex, you know, the prefrontal cortex takes it as high as, as humans can, can abstract.

06:22 - but, but, but all of that is, and those abstracts go very abstract goals, will influence your actions just as much as the very concrete, representations that you store. So, like I said, the prefrontal cortex is communicating with the rest of the brain, and the rest of the brain is communicating with it. So we're, we're constantly bombarded with information, and we have to choose what we're gonna pay attention to and what we're gonna act on

06:48 - and what we're not when we're driving home. And our goal is to stop off and get, you know, some milk. We have to, we have to keep that representation intact and not be distracted by maybe going off and, and doing something else. so there's been a number of studies that show that the prefrontal cortex is the source of that, the signaling. So for example, we've done experiments where, just on the computer

07:14 - or behavioral experiments where you're, where you see information come, you have to ask, you have to remember faces or scenes. but on some trials we say, we want you to remember the faces, and we want you to ignore the scenes and others, we want you to remember the scenes ignore the faces, but you're being presented with faces and scenes. And so if it was just a bottom up system where you're just drawn by everything that comes in,

07:37 - you would just store everything. but what the prefrontal cortex is, is directs you, directs, the brain towards processing the faces when that's relevant and processing the scenes when that that's relevant. It can so efficiently allows you to control, your behavior based on what the rule is or based on what the instructions are, based on what your, your goal is. So again, it's kind of the CEO, it's the conductor that's,

08:00 - of kind of organizing how information's being processed through the brain. So there are a number of neural chemicals that are synthesized in the brainstem. we call these the brainstem modulatory systems. There's acetylcholine, there's dopamine, there's norepinephrine, and all of these, all of these neurochemicals influence the cortex by way they project to the brain.

08:22 - So each of these modulatory systems project to different parts of the brain. And by the way, they project, that's how they influence the brain. So when you look at the dopaminergic neurons in the brain, there's more projections to the prefrontal cortex than any other part of the brain. So dopamine seems to be something specifically acting on the, on the prefrontal cortex. And there's more of these, there's more dopamine receptors

08:46 - in the prefrontal cortex. So it was discovered quite a long time ago that if you deplete dopamine in the brain, you will impair working memory and you'll impair frontal lobe function. Or if you enhance, dopamine, you'll improve, working memory or frontal lobe function. And other transmitters have other functions. So for example, acetylcholine acts on the hippocampus and, and boosting acetylcholine will improve a different type

09:12 - of memory, which is called long-term memory. So dopamine and working memory and functions are intimately tied. What's interesting about dopamine is it also projects to the basal ganglia. And so we know a lot about it because in Parkinson's disease, there's a depletion of dopamine in the striatum, in the basal ganglia, and that leads to all of the motor, findings that we see.

09:34 - But when you deplete it in the prefrontal cortex, you have these cognitive, deficits. And there's this rare, very interesting balance between the prefrontal cortex and the, basal ganglia in terms of its domineer function. It's thought that the, that the, basal ganglia allows us to update our working memory. So when we're holding something in mind, but we have new information, we have to update it.

09:58 - And, the dopa neurotic input into the basal ganglia seems to allow that updating process to happen. Whereas in the prefrontal cortex, what's very important is to hold that information in mind and keep it stable. Don't let it, don't let it disappear. And the pref and the dopaminergic input into the prefrontal cortex allows that stability. So in that way, dopamine allows for the dopamine and the basal ganglia allows for the flexibility that we have in our frontal lo function

10:23 - and the, in our working mem, sorry. And then the, the dour input into the prefrontal corus allows that cognitive stability that we have so that we're able to not be rigid and, and not to be dis distracted. Yeah. So what's very interesting is, is, hormones is a little bit late to the game in terms of frontal lobe function. There's, first was the study of dopamine and later came hormones.

10:48 - There's actually quite a lot of work on the effect of, estrogen on frontal low function. It turns out that there's estrogen receptors all throughout the brain, and there's more estrogen receptors within the prefrontal cortex than any other part of the brain. And it was discovered that if you, that dopamine will increase estrogen activity and increase the estro, I'm sorry, estrogen will increase, dopamine activity and increase the synthesis of dopamine.

11:16 - So the estrogen that's being produced by the pituitary is in turn, modulating, dopamine. And so another, you know, observation is that in postmenopausal women with low estrogen, there is working memory difficulties that can be improved with estrogen treatment. And we've done a number of studies. Emily Jacobs, when she was a graduate of my lab, did a study where she looked at women at different stages

11:43 - of their estrogen cycle and measured their dopamine function and measured their frontal, lo functional FMRI, and showed that when their, their estrogen was the lowest, their Dopamine was the lowest, and their frontal lobe function was the lowest. So hormones become incredibly another important modulator of frontal lobe function in addition to, dopamine, really, I'm a practicing neurologist and I see patients all the time of frontal lobe injury.

12:08 - And I can see the link between these basic mechanisms and what they're, what they show at the bedside or in, in the real world. that wasn't true 30 years ago. It was very perplexing to me, the real life behaviors, trying to link it back. But we've have so much, we've gained so much knowledge over the last 30 years that mechanisms such as working memory impairments or inability to maintain a, a goal or abil

12:35 - or our ability to sort of switch and prioritize you, you can see how that plays out, how that plays out in the real world. So for e example, there's a behavior called imitation and utilization behavior that these patients can have. Dr. Lait, his neurologist in France showed back in the eighties, this behavior very nicely. For example, one, he sat in front of a patient with frontal lobe damage

12:59 - and he put a pair of glasses on the table, and he didn't instruct the patient to do anything with those glasses, and the patient just picked them up and put them on, even though he had a pair of glasses on already. So it wasn't the appropriate context, and he wasn't instructed to do so. And it was even embarrassing. He even brought this patient to his home, just to see what he'd do.

13:20 - And the patient was just walking around. And when he walked into the bedroom, he saw Dr. LA's bed and he just pulled, took off his clothes, pulled off the covers, and jumped in bed. And again, it wasn't the appropriate court, context. We know that where if we're in someone's office or doctor's office and the doctor's out leaves and the phone rings, we don't pick up the phone. If it was our office, we'd pick up the phone. So it's the frontal cortex that maintains the proper,

13:47 - context for how we behave, and it allows us to sort of translate that knowledge into the appropriate act action. And so without that frontal lobe control, we observe these type of, unusual, behaviors in, in our patients that are not socially appropriate. So the, these kind of behaviors, I'm talking about this in parent, we, we call it these executive function deficits or cognitive control deficits when you have damage

14:12 - to the frontal lobes, these, these are all of the abilities that allow us to guide our behavior based on goals and intentions, rather than just be automatically driven by what's around us. So this ability, if to organize, to plan, to set priorities, to monitor our behavior that's flexible and adaptable, this can all be translated into very sophisticated cognitive therapies that can be helpful. So the real breakthrough in my mind is that the cognitive therapies that have been developed,

14:42 - really were based on these fundamental mechanisms of prefrontal function. They weren't, based on just the phenomenology of what we saw. Now they're based on this is what we think the prefrontal cortex does, as I've just explained. And now we're gonna develop therapies that target those mechanisms. So for example, one

15:01 - of 'em is called goal management training, which was developed by Ian Robertson and Brian Levine at the University of Toronto, specifically aimed at sort of, you know, teaching strategies, to learn how to organize and to plan and to set priorities and to monitor your behavior. And so you can learn these strategies by doing progressively more complex tasks over time. You start with individual projects such as planning a mail meal or planning a family reunion.

15:32 - and then you sort of work your way up to sort of more complex tasks. And after doing these therapies, our patients with frontal injury feel significantly, better and do better on executive function tasks. And as you can imagine, we all are not optimized sometimes with our executive function. So this can help us, us, us all. So even when we've done this therapy on healthy elderly, they feel better, they feel they get things done better,

15:58 - they feel more organized. And so I feel it's definitely something we've talked about disease a lot. I think it's also something that can really be embedded into what we do, you know, in school or what we do in our real life or what we do, in the workplace.

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