The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Here are two seemingly unrelated items that have been recently published and reported in the NYTimes.

How to Study

Under the somewhat daunting title “ The Critical Importance of Retrieval for Learning”, a paper in Science described the results of an interesting experiment done at the Department of Psychological Science of Purdue University.

Students were taught words of a foreign language. They were then divided into 3 groups. One group studied once, and then repeatedly tested. The second group studied and re-studied, but never tested. The third studied once, and never re-studied or tested. Here is how the authors summarize their results:

“ Repeated studying after learning had no effect on delayed recall, but repeated testing produced a large positive effect. In addition, students' predictions of their performance were uncorrelated with actual performance. The results demonstrate the critical role of retrieval practice in consolidating learning and show that even university students seem unaware of this fact. ^“

In other words: memorize! Repeat again and again, because that’s how the brain consolidates it information.

How to Teach (and Study) Math

Why are American students always at the bottom of the list in international rating of math proficiency? The National Mathematics Advisory Panel issued a 120-page report ( www.ed.gov/mathpanel ) on the importance of preparing students for algebra, normally taught in the eighth and ninth grades, and its role as a gateway course for later success in high school, college, and the workplace.

The panel members had to navigate between two competing ideologies. Parents and teachers have fought passionately in school districts around the country over the relative merits of traditional, or teacher-directed, instruction, in which students are told how to do problems and then drilled on them, versus reform or child-centered instruction, emphasizing student exploration and conceptual understanding. It said both methods had a role.

The report urges educators to keep it simple: Define a few key topics and teach them until students master them. Along the way, it says, students should memorize basic arithmetic facts and spend more time on fractions and their meaning.

‘Memorize’ we can now readily accept;  The Science paper elegantly proved its importance in learning. But fractions? Why are they that important? Here is the commission chairman's answer:

“Fractions have been downplayed. There's been a tendency in recent decades to regard fractions to be operationally less important than numbers because you can express everything in decimals or in spreadsheets. But it's important to have an instinctual sense of what a third of a pie is, or what 20% of something is, to understand the ratio of numbers involved and what happens as you manipulate it.”

My personal experience

I was educated in the old fashioned, European-style system of, God forbid, ’rote memory’. There is something disparaging about this term; you half expect a smirk to accompany it. Is it because it reminds us of ‘rot’, as in ‘rotten’? Is it because we disparage Asian education as 'rote memory’?

When I was in fourth grade (not fifth grade, as recommended in the report) I was expected to know the multiplication table so well that I did not have to think about the answer—it became instinctual.

When I was in high school, having to take English as a foreign language (I wasn’t asked whether I wanted it or not), I had to memorize Shakespeare’s soliloquies in Macbeth, Hamlet and King Lear. How many native-born Americans know what ‘soliloquy' means?

Did it do me any good? I attribute my understanding of Shakespeare, my love of words and language, my pleasure in reading poetry, to the soliloquies and sonnets of The Bard. I hated it when I had to suffer committing them to memory. But I am eternally thankful to my old-fashioned, uncompromising teachers who despite the stink bombs, the pranks, the schemes, were unrelenting. They gave me a gift that lasted a lifetime.

I remember my son when he was in fifth grade. He had a hard time memorizing anything, but it was no big deal because he was hardly ever expected to know anything by heart. But I drew the line when he struggled with the multiplication table. I still remember the Saturday afternoon when I drilled him until he was on verge of tears, but learn he did. That was unconventional; it was frowned upon, almost child abuse. The idea that just ‘knowing’ it is not good enough, that a child of 11 should also ‘understand’ numbers theory, sounded preposterous to me. Now come the National Mathematics advisory Panel and the scientists at Purdue, and tell us that we were wrong all along. Old fashioned teaching and testing is the way to learn and retain the knowledge for a lifetime of usefulness and enjoyment.

All I can say is: Amen, and it’s about time!

By Dov Michaeli MD, Ph.D

Who hasn’t complained about loss of memory? With increasing frequency, I forget where I left my glasses, what’s her name? Where did I meet him? And for the hundredth time, what’s the name of this bird?

No, it is not incipient Alzheimer’s. I still write blogs, although that’s no proof of a sound mind. I manage a large drug development project, read the newspapers daily and am up on the latest political twist. So what’s going on?

Beware received wisdom

When I went to medical school (UCSF) I was struck by a paper I read claiming that 50% of what we were taught would be either obsolete, or plain wrong, within 5 years; amazing, but true, and not very reassuring to both physician and patient. One of the things I was taught with great certitude was that with age we progressively lose neurons, which make up the gray matter in the brain. True enough even today. It was then a no brainer to conclude that this loss of neurons is responsible for the creeping loss of cognitive function in the elderly. This tidbit of “information” turns out to be part of the 50% that is obsolete, and maybe even wrong.

The nerve cell

A neuron, like any other cell, has a “body”, enclosed by a membrane. It contains a nucleus, where DNA resides, mitochondria, the power plants that provide energy for the functions a neuron performs, and cytoplasm, where proteins are shuttled about and enzymes perform what they are supposed to. But then there is something unique to neurons: they have long projections, some of them inches long (which is enormous in the context of microscopically small cells). These long projections, called axons, serve two purposes: they serve as conduits for a traffic of neurotransmitters and other substances on their way out of the neuron. And, through tiny projections coming off their surface, called dendrites (small branches, in Latin), they make contact with other neurons around them. This is how information, in the form of electrical impulses, is passed around the brain along precisely demarcated circuits and over very long distances. The neuronal cell bodies, where the nucleus and the DNA reside, are the “brain” of the cell; they have a gray hue under the microscope—hence “gray matter”. The axons, on the other hand, are considered conduits only, very much like water or sewer pipes—no “brain” at all. They have a white hue, and are called the “white matter”.

Organization of the brain

The human brain can be divided into major functional regions, each responsible for different kinds of “applications,” such as memory, sensory input and processing, executive function or even one's own internal musing. The functional regions of the brain are linked by a network of white matter conduits. These communication channels help the brain coordinate and share information from the brain's different regions. White matter is the tissue through which messages pass from different regions of the brain.

Scientists have known that white matter degrades with age, but they did not understand how that decline contributes to the degradation of the large-scale systems that govern cognition.

So what’s new?

New research, published December 6, 2007, in the journal Neuron, begins to reveal how simply growing old can affect the higher-level brain systems that govern cognition. The research was conducted by Randy buckner’s group at the Harvard Medical School and the Howard Hughes Medical Institute. As Jessica Andrews-Hanna, a graduate student in Buckner's lab and the lead author of the study stated:
“The crosstalk between the different parts of the brain is like a conference call; we were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another.”
Buckner, Andrews-Hanna, and their colleagues looked at crosstalk in the brains of 93 people aged 18 to 93, divided roughly into a young adult group (18-34 years old) and an old adult group (60-93 years old). The older participants were given a battery of tests to measure their cognitive abilities—including memory, executive function and processing speed. Each person was studied using functional magnetic resonance imaging (fMRI) exams to measure activity in different parts of the brain. fMRI can precisely map enhanced blood flow in specific regions of the brain. Increased blood flow reflects greater activity in regions of the brain that are utilized during mental tasks.
For the task used in the Neuron study, subjects were presented words and were asked to decide whether each word represented a living (e.g., dog) or nonliving (e.g., house) object. Such a task requires the participants to meaningfully process the words.
Buckner's group explored whether aging in the older group caused a loss of correlation between the regions of the brain that — at least in young adults — engage in robust neural crosstalk.
They focused on the links within two critical networks, one responsible for processing information from the outside world and one, known as the default network, which is more internal and kicks in when we muse to ourselves. For example, the default network is presumed to depend on two regions of the brain linked by long-range white matter pathways. The new study revealed a dramatic difference in these regions between young and old subjects. “We found that in young adults, the front of the brain was pretty well in sync with the back of the brain,” said Andrews-Hanna. “In older adults this was not the case. The regions became out of sync and they were less correlated with each other.” Interestingly, the older adults with normal, high correlations performed better on cognitive tests.
According to the authors, it is inferred that in a young, healthy brain, signals are readily transmitted by white-matter conduits. As we age, those conduits are compromised. Depending on the networks at play, the result may be impaired memory, reasoning or other important cognitive functions. Buckner and Andrews-Hanna emphasized that other changes in the aging brain may contribute to cognitive decline. For example, cells' ability to express chemical neurotransmitters may also be compromised.

My take

1. Extremely important work. The dogma that “dropped neurons” is solely responsible for the cognitive deficits of normal aging simply did not make sense. First, the billions of neurons in the brain have plenty of capacity to make up for losses; we have a tremendous reserve. Second, the brain has the capacity to reroute specific information through alternative circuits if the original ones are compromised in any way. This is what underlies the phenomenon called “brain plasticity”, which is the basis for rehabilitation of stroke victims, or the educational strategies for dyslectic children.

2. This finding, like any in science, raises new questions. What is the nature of the disruption in the default network? Is it reduced number of axons due to neuronal death? Is it a functional defect in the conductive properties of the axons? Is the dysfunction generalized or restricted to specific pathways? What is the root cause of the changes? How can they be avoided?

What can we do about it now?

No doubt you have encountered claims of “brain rejuvenation”. Just work on your daily crossword puzzle, learn a new language, solve sudoku puzzles, stand on your head. The trouble with all these is that they work—but very specifically. If you do your daily crossword puzzles or sudoku you’d be good at them, but you will still forget names and misplace your car keys.

So far, the most convincing global change in the aging brain is reduced blood supply. Blood vessels either get occluded (atherosclerosis) or degenerate because of death of tissue they had supplied. Not surprisingly, the only strategy that proved effective in maintaining the overall integrity of cognitive function is, you guessed it, increase blood supply through aerobic exercise.

So throw away your sudoku puzzle or crossword puzzle and go out for a brisk walk or run. And don’t forget the keys to the house.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

Remember George Orwell’s society, subdued by Big Brother’s complete control of thought and feeling? 1984 came and went, and nothing happened; we dodged the bullet. Or did we?

Memories…

“I cannot but remember such things were,

That were most precious to me”

Macbeth, William Shakespeare.

One of the fondest memories of my youth is dancing a tango called “memories” (I’m giving away my age) in a sidewalk café on the Mediterranean coast on a warm summer evening. Strange what our brain chooses to retain forever…Even stranger is what experiences most of us forget, while others remember forever. I am talking about Post Traumatic Stress Disorder or PTSD, which many of us participating in the horrors of war easily forgot while others are doomed to re-live them again and again. Why?

What long term memories are made of.

It has been generally accepted that long term memories are maintained in the brain by structural changes in the synaptic connections between neurons. You can actually see them in a microscope; the neuronal connections that contain the information of a particular memory become thickened as a result of protein synthesis, and once formed it is very hard to get rid of them. In other words, they are ’long term’. As it commonly turns out in biology, this is not the whole story.

Cherché le enzyme

As always, behind every successful feat of biology there is an enzyme. It’s true of memory, as well.

It has been known for a while that the enzyme PKMξ (which for us mortals is Phosphokinase M zeta) and other similar enzymes are required for the early stages of memory formation. But it was always thought that once the thickened connections are formed, nothing else is needed to retain those memories. Now comes an international team of neuroscientists from the U.S. and Israel (Science, vol. 317, pp. 951-953, 2007) and reports that PKM zeta is essential to the maintenance of long term memory. They fed rats with a saccharin solution, which rats simply hate (can you blame them?). They followed up 40 minutes later with nausea-inducing lithium, just to make sure. They then injected into the cerebral cortexes of half the group with a compound called ZIP, which inhibits PKM zeta, and the other half with a placebo. As long as the experiment lasted (25 days) the group injected with ZIP, thePKM zeta inhibitor, had no memory of the bad experience, and drank again and again from the nauseating elixir. The placebo group avoided it like the plague.

“Remember thee?

Ay, thy poor ghost, whiles memory holds a seat

In this distracted globe. Remember thee?

Yea, from the table of my memory

I’ll wipe away all trivial fond records.”

Here is Hamlet, tormented by the memory of the assassination of his beloved father, trying to selectively wipe out fond memories so as to accentuate the pain and seek revenge. Great poetic drama, but is it possible?

The implications of the report in Science are literally mind boggling. It is quite simple to inhibit all long term memory formation by inhibiting the formation of the thickened connections between neurons through the use of protein synthesis inhibitors. But this is tantamount to killing a mosquito with a hydrogen bomb; you, and your memories, will be wiped out.

Now that we have an enzyme as a potential target, it is only a question of time before specific enhancers and inhibitors will be synthesized. Now we are talking “smart bombs” rather than nukes. How wonderful would it have been if instead of memorizing Hamlet and Macbeth in high school I could just pop a pill enhancing PKM zeta’s activity? Or, wouldn’t it be great if we could cure all our traumatized war veterans with a simple drug inhibiting the enzyme, something like ZIP?

It’s not so simple

On the neurobiological level, we still don’t know that we can be selective. We don’t know if we can wipe out unwanted memories and retain the rest. But this is eminently susceptible to testing, and I am sure will be done in short order. Sorry Hamlet, you have been waiting for 400 years; wait a few more.

But a deeper question, and less prone to unequivocal answers, is the psychological, ethical, and moral question: do we want it? On the one hand, we witness the torment of our Vietnam and Iraq veterans suffering from PTSD, and we reflexively answer: of course! But ask Eli Wiesel if he would want to forget the Holocaust. Who would be witness today to the horrors of yesteryear? Or would Primo Levi write his masterpiece If This be a Man or Survival in Auschwitz if he simply wiped out his horrible memories? Oh, yes; Primo Levi finally succumbed to the recurring torment of his private hell and committed suicide. Would he would have preferred to forget it all?

And on a political level: do you trust governments to resist the temptation of suppressing ‘inconvenient truths’ with an easily administered pill? The Russian government reverted to the Soviet practice of interning investigative journalists in psychiatric wards. What if they wanted to wipe out any memories of inconvenient revelations by the courageous journalists? What if our soldiers were ordered to take the pill after every brutal engagement?

These are tough questions. Science is neither good or bad; it is neutral. What we do with it is fraught with bright promise and dark danger. What shall we choose?

Dov Michaeli, MD, Ph.D is a scientist in the biotech industry.

We were watching tonight a great program on PBS about Billie Jean King and her wonderful tennis career. Her 1973 match, or dare I say grudge match, against Bobby Riggs, was a delight to the eyes and the soul. We relished her strategy of running ragged this aging fool from one end of the court to the other. There she was: a skilled, rebellious young woman facing a male chauvinist who taunted her to test her mettle against his. But the match had a much larger meaning; it was emblematic of the new generation, of a new world upending the old order and its tired prejudices, not in a bloody revolution fought in the streets—but in a fair, civilized match on the tennis court. How many of you remember a single feminist demonstration? but we all remember this historic match; such was its impact.

However riveting her life story was, what caught my attention was her secret weapon: her tremendous ability to focus, to remain calm under pressure, in fact to relish stressful situations. As she herself said, minutes before a match all her anxieties and insecurities would be replaced by determined calm and focused planning. How could she do that?

It’s all in your head

The neurons in our brain talk to each other through chemicals that are called neurotransmitters. One of those is called dopamine, and its function is invaluable; when we have a pleasurable experience of any kind, dopamine is released. We thus learn to associate this experience with reward and pleasure and tend to repeat it. This is important to our brain’s unconscious decision- making. Just think of it: if on every occasion that we encountered a delicious meal, or a glass of wine, or making love, we had to gingerly try it first to see if we liked it—we would be paralyzed with indecision. Billie Jean King did not have to convince herself that she loved the game every time she stepped on the court—her brain had already made this decision for her.

What happens when dopamine levels in the blood are elevated?

The physiological and psychological effects of elevated dopamine are wonderful: a sense of optimism, exhilaration, even euphoria; a sense of increased energy that can escalate to hyperactivity, sleeplessness, loss of appetite, increased heart rate and hyperventilation. As part of this behavioral complex, there are a few other traits: extremely focused attention, motivation and goal-directed behavior. Do you recognize these as ‘symptoms’ of falling in love? Can the pounding heart be the reason for the association of love with the heart? Can it explain the rapt attention of the young lover earnestly listening to her mate’s nonsense?

What about Billie Jean’s uncanny ability to focus on the game? She loved the game, she was in love with it. And I’d bet her dopamine levels were sky high as well.

It is a cliché that love made the world go round. Unfortunately, my friend, I hate to disillusion you—it’s all in the dopamine.

Dov Michaeli MD, Ph.D