The Doctor Weighs In

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 This tidbit of “information” turns out to be part of the 50% that is obsolete, and maybe even wrong.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

On November 11 I read an Op Ed article in the New York Times titled “This is Your Brain on Politics”. Being interested in neurobiology, and an addict of all things political, I homed in like a laser beam: is this the holy grail of neuroscience? Are we capable of deciphering our innermost thoughts (in this case, political thoughts) using brain imaging techniques?

The article was written by three neuroscientists: Marco Iacoboni, Joshua Freedman and Jonas Kaplan of the University of California, Los Angeles, Semel Institute for Neuroscience; a communications professor, Kathleen Hall Jamieson of the Annenberg Public Policy Center at the University of Pennsylvania; and Tom Freedman, Bill Knapp and Kathryn Fitzgerald of FKF Applied Research.

The experiment

The authors used functional magnetic resonance imaging (fMRI) to scan the subjects' brains while they viewed images of political candidates. This imaging technique can be used to measure changes in oxygenated blood and hence to infer changes in metabolic activity in different parts of the brain. Some parts of the brain reliably alter their activity under certain conditions, and scientists have used this fact, along with information drawn from other techniques in both humans and animals, to document which brain area is associated with which cognitive function. For example, greater activity in the insula is often reported when people experience disgust, whereas more activity in the amygdala is reported when people are anxious.

While in the scanner, the subjects viewed political pictures through a pair of special goggles; first a series of still photos of each candidate was presented in random order, then video excerpts from speeches. Then they were shown the set of still photos again. On the before and after questionnaires, subjects were asked to rate the candidates on the kind of 0-10 thermometer scale frequently used in polling, ranging from “very unfavorable” to “very favorable.”

The results

Here are some excerpts from the findings:

1. Voters sense both peril and promise in party brands. When we showed subjects the words “Democrat,” “Republican” and “independent,” they exhibited high levels of activity in the part of the brain called the amygdala, indicating anxiety. The two areas in the brain associated with anxiety and disgust — the amygdala and the insula — were especially active when men viewed “Republican.” But all three labels also elicited some activity in the brain area associated with reward, the ventral striatum, as well as other regions related to desire and feeling connected. There was only one exception: men showed little response, positive or negative, when viewing “independent.”

2. Emotions about Hillary Clinton are mixed. Voters who rated Mrs. Clinton unfavorably on their questionnaire appeared not entirely comfortable with their assessment. When viewing images of her, these voters exhibited significant activity in the anterior cingulate cortex, an emotional center of the brain that is aroused when a person feels compelled to act in two different ways but must choose one. It looked as if they were battling unacknowledged impulses to like Mrs. Clinton.

Subjects who rated her more favorably, in contrast, showed very little activity in this brain area when they viewed pictures of her.

This phenomenon, not found for any other candidate, suggests that Mrs. Clinton may be able to gather support from some swing voters who oppose her if she manages to soften their negative responses to her. But she may be vulnerable to attacks that seek to reinforce those negative associations.

7. John Edwards has promise — and a problem. When looking at pictures of Mr. Edwards, subjects who had rated him low on the thermometer scale showed activity in the insula, an area associated with disgust and other negative feelings. This suggests that swing voters’ negative emotions toward Mr. Edwards can be quite powerful .

Oh, Yeah?

Take John Edward’s “problem”, for example. Is the fact that the insula showed higher activity dooms his campaign? increased activity in any brain area is rarely exclusive to any one function. That insula activity did not necessarily mean the subjects were disgusted. Insula activity has also been associated with drug craving, the taste of chocolate, pain and the quality of orgasm (!). Not necessarily such bad news after all.

This is not “junk Science”; it is purely junk

The authors wouldn’t dare publish such an article anywhere else but on an Op-Ed page; a peer-reviewed journal would send a rejection notice by return mail.

Here is a response of Brandon Keim in Wired science magazine:

“As science, it was a joke. As political theory, it was shallow. As an op-ed, it should have been thrown out at first glance. Uninformed opinion is tolerable in an editorial, but not when it purports to be validated by bad science .”

And the response of 14 heavy-weight neuroscientists:

“The results reported in the article were apparently not peer-reviewed, nor was sufficient detail provided to evaluate the conclusions.

As cognitive neuroscientists, we are very excited about the potential use of brain imaging techniques to better understand the psychology of political decisions. But we are distressed by the publication of research in the press that has not undergone peer review, and that uses flawed reasoning to draw unfounded conclusions about topics as important as the presidential election .”

Why shame on the NYT?

After all, you might think, why not open a window of expression to all scientific observations, valid or not? We do publish rubbish like “intelligence design”, or “creationist theory” side by side with “evolutionary theory”. As chief Justice Brandeis famously said: sunshine is the best disinfectant. But as Nature magazine stated: “What is troubling about the NYT is that the results described in the op-ed are apparently the claims of a commercial product posing as a scientific study. This is only partially transparent. Three of the authors list their affiliation with FKF Applied Research, a company based in Washington DC that is notorious for using similar brain-scan analysis to conclude which TV adverts (pardon the Britishism) aired during a major sporting event were most effective. In its own words, the company is a "business intelligence firm selling fMRI brain scan-based research to Fortune 500 companies".

More troubling for a mainstream newspaper that prides itself on its balanced reporting is the absence of declarations from three other authors. Rightly listed as affiliated to a neuroscience institute at the University of California, Los Angeles, one is also a co-founder of FKF Applied Research and all three, according to a previous publication, have benefited from funding from the company.”

Any harm done?

Yes, and yes. First, harm was done to the reputation of Science as a self-monitoring and self-correcting mechanism, whose only fealty is to the Truth. It gives credibility to political hacks in Congress and other branches of the government who claim that global warming is a figment of statistical models conjured up by “UN scientists”, that Evolution is “only a theory” propagated by atheist-scientists, that the medical harm of tobacco smoking is not supported by credible evidence, and so on and so on. In a day when the assault on science has not reached such a magnitude since the days of the medieval church—we don’t need to provide more weapons for their armamentarium.

And second: The “Twinkies Defense”, used in supervisor Dan White’s defense of his murder of S.F. mayor John Moscone and supervisor Harvey Milk, was a harbinger of things to come. This junk science was presented to the court by a psychologist-“scientist”. Brain imaging “evidence” is now being presented in court by hired gun-“neuroscientists”. Genetic information is being twisted beyond recognition in the service of racists and other malevolent rabble.

This is why an article such as this one is not just an innocent romp through neuroscience and politics, maybe even with a faint sense of humor. It is harmful, and shame on the NYT for publishing it.

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

By Dov Michaeli MD, Ph.D

“Methought I heard a voice cry ‘Sleep no more!

Macbeth does murder sleep’—the innocent sleep,

… The death of each day’s life, sore labor’s bath,

Balm of hurt minds, great nature’s second course,

Chief nourisher in life’s feast”

Macbeth, William Shakespeare, 1600 AD.

Four hundred years later UC Berkeley scientists used brain imaging techniques to explain Lady Macbeth’s sleep-deprived brain descent into the darkness of insanity. They studied 26 young adults, half of whom were kept awake for 35 hours straight and the other half were allowed a normal night’s sleep in that same time period. Their brain was then studied using fMRI imaging. This technique shows the blood flow to different areas of the brain, and by extension, their state of activation.

What did they find?

The amygdala is the area in the brain that deals with unpleasant (or aversive) emotions, and puts the body on alert to protect itself. For instance, feelings of fear or rage are processed there. In the sleep-deprived subjects this area “lit up”, showing a high activation state.

On the other hand, the prefrontal area is responsible for tamping down those feeling, of adding some rationality into the mix; in a word, the outcome of its intervention is what we call ‘judgment’. In the sleep-deprived subjects the level of activation of the prefrontal cortex was significantly reduced.

Subjects who had gotten a full night of sleep showed normal brain activity.

This is not surprising to anybody who has experienced sleep deprivation, and that’s essentially all of us. Who hasn’t experienced the easy irritability, or alternatively the giddiness, that come after a sleepless night? Or the compulsive and nervous eating? Or the feeling that your “resistance is down” and that you are prone to a viral cold? These feelings are not “all in you head”. Sleep deprivation has been shown to affect emotional well-being, to alter metabolic control, and to adversely affect the part of the immune response (called innate immunity) that protects us from bacterial and viral infections.

There may be more to it

If the capacity to tamp down negative thinking is impaired, it opens up the possibility of a connection to psychiatric disorders like depression and anxiety. If you think of it, both of these disorders are a reflection of inappropriate or exaggerated negative response to a stressful event. Such events need not be dramatic, they could be quite trivial. A not-so-good grade at school, perceived slight from a friend, a critical remark by a coworker—all these can precipitate depression or anxiety. And the brain mechanism is identical to that of sleep deprivation: an imbalance between the negative messages flowing from the amygdala, and the moderating and rationalizing effect of the prefrontal cortex.

America the sleepless

How much sleep do we need? It varies with age and overall health. Most adults require 7- 8 hours a night. Older people may need 5-6 hours. Teenagers may require an hour or so more. Now consider the following:

· The National Sleep Foundation poll found that in 1998 35% of adult Americans got at least 8 hours of sleep a night. In 2005 this figure dropped to 26%.

· About 40% of Americans get less than 7 hours of sleep.

· 75% reported having some sleep disorder one or two nights a week.

These are sobering statistics. I can’t help but wonder if our chronic sleep deprivation is not a contributing factor to our elevated level of societal rancor, increased violence, our deteriorating civility, and our increased rate of diagnosed psychiatric disorders such as chronic depression, anxiety and sociopathic behavior.

Sleep has become synonymous with sloth in our “on the go” society. It would take more than academic studies to change this culture. We need nothing less than a paradigm shift in our outlook on life.

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

By Dov Michaeli MD, Ph.D

Leptin is a hormone secreted from fat cells that provides information to the brain about energy stores. If energy stores are abundant, circulating levels of leptin are high, and the brain’s response is reduced food intake. On the other hand, in the fasted state leptin levels are low, and the response is increased food intake. It had been known that the regions of the brain where leptin exerts its influence are the nucleus accumbens and the associated nerve bundles called the striatum, regions where the reward/pleasure centers are located (and are the seat of addiction as well). However, there is little or no information about how these  brain centers integrate leptin’s signal with the rewarding properties of food.

Now a group of scientists from Cambridge university in the UK provided the missing link. In a paper published recently in Science they report on a study done on a 14 year-old boy and a 19 year-old girl who suffered from a very rare condition of leptin deficiency. This condition causes hyperphagia or excessive eating and gross obesity. But when they were injected with synthetic leptin eating was reduced to about normal levels. The investigators used fMRI (functional MRI) to visualize the nucleus accumbens and striatum. They presented the subjects with visual images of food, and for control-- visual images of non-food, in the leptin-deficient and leptin-treated states. They used a 10-cm visual analog scores to rate hunger, satiety, and the “liking” of the various food images.

And the results…

What they have shown is that leptin markedly affects neural responses to visual food stimuli; the appropriate reward centers showed markedly elevated blood flow, indicating increased metabolic activity in those regions. The responses to the questionnaire rating hunger, satiety and “liking” of the food images indicated that leptin did not affect the “liking” but rather the “wanting” of food. In the leptin-deficient state, images of well-liked foods engendered a greater wanting response, even when the subject had just been fed. After leptin treatment, well-liked food images engendered this response only in the fasted state. Thus, wanting of food appears to drive the correlation between activation of the reward centers and liking.

Why is it important?

At first blush, the whole exercise looks like splitting hairs: what difference is there between wanting and liking a food? My son used to hate anything that lived in water. But when he was famished enough he wolfed down a salmon steak and asked for more. In neurobiological terms, his low leptin level told his brain: you want this fish, liking it is not an issue right now. Which reminds me of a conversation I had with an orthodox rabbi about arranged marriages. What about love, I asked. That will come after the wedding, he answered.

From an evolutionary point of view it makes a lot of sense. Roaming the Savannah in search of food after several days of fasting there is no advantage in being too choosy; just give me that piece of meat, and I don’t care where it came from. I suspect that liking a certain food is a relatively recent addition to our behavioral repertoire, after the invention of agriculture about 10,000 years ago and the availability of reliable and abundant supply of food. Before that we didn’t eat—we devoured.

Dov Michaeli MD, Ph.D is in the Biotech industry, and he really likes good food.

By Dov Michaeli MD, Ph.D

No, I haven’t become a “new age”, “positive thinking”, “psychic energy” guy. I have seen a lot of willpower, grit and optimism overcome physical limitations—but that does not correct a physical limitation. Wouldn’t a way to change the brain’s perception of pain, or alter the brain’s pathways that determine an addictive behavior be a better solution than the panoply of drugs that we addle our brain with?

Technology to the rescue

One of the advantages of living in Northern California is being plugged in to the new and emergent technologies that are all around us. Superb universities that are incubators of revolutionary ideas, startup companies budding all over the place like mushrooms after the rain, many of them folding, other going on to do great and wonderful things (heard about the latest one? It has a funny name, something like Google)—what an exciting time and place to live in.

So it was really just a question of time before somebody took a stab at exploiting the brain’s plasticity (its adaptability or capacity to change) in order to deal with medical and psychiatric problems. Indeed, several startups are already hard at work doing just that.

How do they do it?

The technique of fMRI or functional MRI measures the blood flow in different regions of the brain, and displays it on a screen. This is how radiologists can determine areas in the brain that are metabolically hyperactive (pain perception, hunger, thinking) or hypoactive (stroke, some tumors). But now, a few companies are developing ‘real-time fMRI’, which means that you can view your own brain MRI in, well, real time. And that opens up some exciting possibilities.

Remember the old EEG (electroencephalogram) biofeedback technology? Subjects would be hooked up with electrodes which measure electrical feedback across the brain. They would then use a visual representation of the brain waves to control their blood pressure, for instance, using techniques of biofeedback such as meditation or visualization. The results were encouraging but were not translated to clinical use.

The new fMRI technique actually shows the subject which areas of the brain have increased blood flow if they suffer from chronic pain, for instance. The patient lies inside the scanner and watches a computer-generated flame projected on the screen of virtual-reality goggles; the flame’s intensity reflects the neural activity of regions of the brain involved in the perception of pain. Most people can control the flame’s intensity by concentrating and using visualization techniques. One could imagine bathing the neurally active region with a soothing drug, or dousing the area with a cold liquid, the flame would wane and patient would feel relief of the pain. Amazing but true.

This is actually an old concept. Paul Eckman, a professor of psychiatry at UCSF, wrote extensively about the mutual interaction between the body and the brain. We know, for instance, that a happy thought brings a smile to our face. But he showed that conversely, using the facial muscles involved in smiling activates the pleasure/reward centers in the brain. Result: you feel happy for no reason at all. Just try smiling every morning, or singing “Oh, what a beautiful morning” when you get out of bed, and you’d be amazed at the results. I read a few years ago about an Indian man who would go out to the park, and would laugh out loud without any reason. He claimed that it put him in a happy frame of mind for the rest of the day. Soon, other people joined him. They formed a laughing club, meeting daily in the park. This laughter became infectious, and thousands of people around the globe formed their own clubs. Sounds wacky, but it works, and it has a neurobiological basis. Try it!

The possibilities are mind boggling

What else can be controlled?

• I already mentioned the craving for drugs; addiction should be eminently amenable to this technique, since it is restricted to distinct brain regions.
• Hunger and feeding control.
• Psychiatric diseases such as depression.
• Behavioral disorders, such as uncontrolled anger, fear, phobias.
• How about stroke? Recent experiments have shown that by forcing stroke patients to use their paralyzed limb rather than the functional one, they begin to regain function. Underlying this “miracle” is the capacity of the brain to adapt and generate new pathways to serve the functions of the damaged ones. One problem with these experiments is that improvement is painfully slow and uneven. It is quite plausible the visualization of the new areas, which should have increased blood flow, could improve the outcome of these experiments.

I am sure that assorted libertarians and privacy watchdogs will warn about the sinister possibilities of this kind of brain control. Frankly my dear reader, I don’t…Just smile and be happy.

Dov Michaeli MD, Ph.D is in the biotech industry and is engaged in development of pain control medication.