Soundview Psychiatric | Seattle Mental Health Services

Raising a toast to the human brain

John Medina — Tue, 08 May 2012 23:22:00 +0000

John Medina discusses Brain Rules with Warren Etheredge at The High Bar.

Brain Rules for Meetings

John Medina — Tue, 31 Jan 2012 06:14:00 +0000

Molecular biologist John Medina, speaker and author of the best-selling book Brain Rules: 12 Principles for Surviving and Thriving at Work, Home, and School, didn't set out to become a media star. But he got so fed up with encountering myths about the brain - that you use only 10 percent of it, for example, or that there are right- and left- brain personalities - that he once threw a magazine across a seat on an airplane. (The flight, he notes, wasn't full.) "So I decided to write Brain Rules," Medina said, "as an attempt to say, ‘Look, here's what we do know, here's what we don't know, here are a few things you can try that might have an application in the business world - and the meetings world as well.'"

Not that Brain Rules will tell you how the brain operates. "We don't know squat about how the brain works," said Medina, who has focused on brain research for nearly three decades. He added: "I don't know how you know how to pick up a glass of water and drink it. But we do know the conditions that [the brain] operates best in, even if we don't know all the ins and outs of that operation."

Which of the 12 Brain Rules has the most impact on meetings?
Well, probably, the biggest one would have to be about attentional states. This rule is very simple: People don't pay attention to boring things. So if you really want to have a lousy meeting, make sure it's boring. If you want to have a lousy classroom, make sure it's boring. And if you want to vaccinate against the types of things that really do bore the mind, we have some understanding of that.

So how do you design a good meeting?
Here are the top three "brain gadgets" that probably have a bearing on the question. First, the human brain processes meaning before it processes detail. Many people, when they put meetings together, actually don't even think about the meaning of what it is they're saying. They just go right to the detail. If you go to the detail, you've got yourself a bored audience. Congratulations.
Second, in terms of attentional states, we're not sure if this is brain science or not, but certainly in the behavioral literature, you've got 10 minutes with an audience before you will absolutely bore them. And you've got 30 seconds before they start asking the question, "Am I going to pay attention to you or not?" The instant you open your mouth, you are on the verge of having your audience check out. And since most people have been in meetings - 90 percent of which have bored them silly - they already have an immune response against you, particularly if you've got a PowerPoint slide up there.

How do you then hold attention?
This is what you have to do in 10 minutes. You have to pulse what I just said - the meaning before detail - into it. I call it a hook. At nine minutes and 59 seconds, you've got to give your audience a break from what it is that you've been saying and pulse to them once again the meaning of what you're saying.

What is the third "brain gadget"?
The brain cycles through six questions very, very quickly. Question No. 1 is "Will it eat me?" We pay tons of attention to threat. The second question is "Can I eat it?" I don't know if you have ever watched a cooking show and have loved what they are cooking, but you pay tons of attention if you think there's going to be an energy resource. Question No. 3 is highly Darwinian. The whole reason why you want to live in the first place is to project your genes to the next generation - that means sex. So Question No. 3 is "Can I mate with it?" And Question No. 4 is "Will it mate with me?"

It turns out we pay tons of attention to - it actually isn't sex per se, it's reproductive opportunity. [It is also] hooked up to the pleasure centers of your brain - the exact same centers you use when you laugh at something. Oddly enough, I think that's one of the reasons why humor can work. If you can pop a joke or at least tell an interesting story, it's actually inciting those areas of the brain that are otherwise devoted to sex. You don't become aroused by listening to a joke. I'm saying those areas of the brain can be co-opted. You can utilize them, and a good speaker knows how to do that.

What are Questions 5 and 6?
"Have I seen it before?" and "Have I never seen it before?" We are terrific pattern matchers. There is an element of surprise that comes when patterns don't match, but the reason why that happens is because we are trying to match patterns all the time.

Is there a Brain Rule that addresses whether you should try to control the use of laptops and phones during a meeting session?
I have this rule response, based on data, and then I have a visceral response, also based on data. In other words, I'm about ready to tell you a contradiction. Are you ready?

Yes, I am.
Alrighty. I do believe what you can show is that there are attentional blinks. The brain actually is a beautiful multitasker, but the attentional spotlight, which you use to pay attention to things, [is not]. You can't listen to a speaker and type what they are saying at the same time.

What you can show in the laboratory is that you get staccato-like attentional blinks. Just like you come up for air: You look at the speaker, then when you're writing, you cannot hear what the speaker is saying. Then you come up for air and hear the speaker again. So you're flipping back and forth between those two, and your ability to be engaged to hear what a speaker is saying is necessarily fragmented.
At the same time, if your speaker is boring, you could have checked out anyway. So you see, in many ways it depends upon the speaker.

How so?
If the speaker is really compelling and is clear and is emotion- ally competent, and has gone through those six questions, letting you come up for air every 10 minutes, I've actually watched audiences put their laptops away just to pay attention.

I have a style that is purposely a little speedier. And the rea- son why is that it produces a tension that says, "I need to pay attention closely to him or I'm going to lose what he's saying." I don't make it so fast that it's unintelligible - at least I hope I don't. But I do make it fast, and occasionally I see comments that say, "Great speaker, but you know, you were too freaking fast."

This interview originally appeared in the Professional Convention Management Association (PCMA) magazine Convene.

Soundview is moving

Dr. Madhavan — Fri, 16 Dec 2011 17:41:36 +0000

Starting January 2nd, my office will be moving to 620 Kirkland Way, Suite 202, Kirkland, WA 98033.

The new office is about 4 miles from the current location. The new office has a parking lot that is easier to access and will have features designed to provide a more discrete entry and exit. My practice has always been about combining highly effective psychiatric treatment with a thoughtful and comfortable patient experience. This move is an opportunity to more fully realize this vision.

What Humans Can Learn From Monkeys

John Medina — Fri, 02 Dec 2011 03:07:00 +0000

We are exploring the sometimes creepy, always fascinating distance between genes and behaviors. In this entry, I wish to illustrate a dramatic example of how nature and nurture interact, not by examining humans, but by considering some genetic next-door neighbors: vervet monkeys. This is a great example of “Learn from your parents — it’s good for you!” without a human parent in sight.

Vervet monkeys have interesting predator vocalizations, and even something of a vocabulary. The animals appear to be born with this ability — there’s our nature. As we shall see, however, the application requires some practice — and that’s our nurture. This is easily seen in vervet monkey foraging behaviors, whether the animals are searching for food on the ground or in the trees.

Vervet monkeys have a vocalization for the warning “Run, you idiot, there’s a snake on the ground!”, for example. When an adult vocalizes this warning, the whole tribe runs into the trees, and everyone is safe. They have another word for “Run, you idiot, there’s a predatory bird in the air!” When an adult vocalizes this warning, the whole tribe dives to the ground, and everyone is safe one again.

Note that I italicized the word “adult” throughout the previous paragraph. That’s because when the tribe hears a youngster vocalize either the snake or bird warning, the tribe doesn’t do anything. The members wait until they hear an adult say it. Why do they pause? Because the little ones often get the vocabulary mixed up. They have not yet learned the correct application of their handy early warning system.

The adults aren’t trying to be obnoxious. They are trying to avoid a disaster. Imagine the tragedy if the whole tribe responded to a juvenile’s call to hit the dirt when the little guy saw a snake. The funny cartoon version has him saying sheepishly, “Oops. I meant, trees” — but the deadly real world version is “no more tribe.” Little vervets may be born with the ability to warn others, but they have not yet been instructed on its proper use. They will eventually learn the correct behavior by persistent interactions with older members of the tribe, but the instruction set is not innate. They may have been born with pre-loaded vocalizing software. That doesn’t mean they know how to use it.

A very similar situation between biological ability and social experience is observed with humans, examples of which we will explore in the next few entries. We may come into this world with some pretty sophisticated DNA, but like our primate cousins, that is no guarantee we know how to use it.

How do you get a baby to sleep through the night? We have no idea.

John Medina — Sat, 05 Nov 2011 01:27:00 +0000

I am often asked why Brain Rules for Baby doesn't include advice on how to get your child to sleep through the night. The omission is deliberate, and my recent answer to one reader's question via e-mail explains the reasoning. I thought you would like to see the answer, too. Thanks for all of your interest in the book. It means a great deal.
-- John

Dear Reader;

You raise an important issue regarding sleep, one of the most critical in the early months of child-rearing. Unfortunately, I cannot give a response equal to its criticality.

If you are having problems with getting your child to sleep through the night, you have probably read everything you could on the issue. In that journey, you might have noticed there are many different opinions about how to get kids to sleep through the night - often by experts in the field. You might further have noticed that these well-established researchers and clinicians often appear to say contradictory things. The advice can almost be put into a continuum. On one end, there are researchers like Dr. Richard Ferber, interpreted as saying draconian things like “let your kid tough it out at night” (that’s hardly a fair characterization, by the way). On the other end is pediatrician William Sears and family who is interpreted as saying “respond to every demand at night” (also hardly a fair characterization). Here are the two references from these seasoned medical professionals, which make great comparative reading for the views they hold:

“Solve Your Childs’ Sleep Problems”,

Richard Ferber, 2006

and

“The Baby Sleep Book”

William Sears et al, 2005

Why the contradiction? BECAUSE NOBODY REALLY KNOWS HOW TO ADDRESS THE SLEEP ISSUE. There does not appear to be a one-size-fits-all answer, which is why any advice which claims to be THE ANSWER does not pass my “grump factor”, as a scientist. My standard response, therefore, is to appeal to the wisdom of the real expert, the parent – YOU – and say something like “Every brain is wired differently from every other brain. Go out and buy both of these books and expose yourself to the various recommendations. Then determine which strategies (or combinations of strategies) your child – based on your knowledge – is most likely to respond. Try these strategies in a systematic fashion, and progressively design new ones until you find the strategy that does work.”

I have an example of this flexible, deliberate approach in my own child-rearing experience.

It was almost seven months before my eldest child slept successfully through the night. What worked for me was to give him a “modified” Ferber protocol – a gentler version of his recommendation, which took almost a week to execute successfully (I literally took off time from work to do it, relieving my poor exhausted wife).

My youngest child also had trouble getting to sleep. But when I tried my “modified” Ferber strategy, it did not work for him. What did the trick was a modified “Sears” strategy. And it also took about a week to become successful too. Living proof for the fact there is no over-arching strategy that will work for every child.

I wish you well. Solving this riddle is one of the toughest tasks in the early years of child-rearing.

John Medina

Why is it So Hard to Get Kids To Do the Right Thing? (VIDEO)

John Medina — Wed, 13 Jul 2011 17:19:00 +0000

If children are born with a sense of right and wrong, as brain science shows, why don't they just do the right thing?

Part of the reason it's tough is that the moment children observe bad behavior, they have learned it. Even if the bad behavior is punished, it remains easily accessible in the child's brain. Psychologist Albert Bandura was able to show this with help from a clown.

In the 1960s, Bandura showed preschoolers a film involving a Bobo doll, one of those inflatable plastic clowns weighted on the bottom. In the film, an adult named Susan kicks and punches the doll, then repeatedly clobbers it with a hammer. After the film, the preschoolers are taken into another room filled with toys, including (surprise) a Bobo doll and a toy hammer.

What do the children do? It depends. If they saw a version of the film where Susan was praised for her violent actions, they hit the doll with great frequency. If they saw a version where Susan got punished, they hit Bobo with less frequency. But if Bandura then strides into the room and says, "I will give you a reward if you can repeat what you saw Susan do," the children will pick up a hammer and start swinging at Bobo.

Whether the children saw the violence as rewarded or punished, they learned the behavior. Bandura calls this "observational learning," and his finding is an extraordinary weapon of mass instruction. Observational learning plays a powerful role in moral reasoning.

How does moral reasoning develop? Slowly. Harvard psychologist Kohlberg believed that moral reasoning depended upon general cognitive maturity--another way of saying that these things take time. He outlined a progressive process:

1. Avoiding punishment. Moral reasoning starts out at a fairly primitive level, focused mostly on avoiding punishment. Kohlberg calls this stage pre-conventional moral reasoning.

2. Considering consequences. As a child's mind develops, she begins to consider the social consequences of her behaviors and starts to modify them accordingly. Kohlberg terms this conventional moral reasoning.

3. Acting on principle. Eventually, the child begins to base her behavioral choices on well-thought-out, objective moral principles, not just on avoidance of punishment or peer acceptance. Kohlberg calls this coveted stage post-conventional moral reasoning. One could argue that the goal of any parent is to land here.

This willingness to make the right choices--and to withstand pressure to make the wrong ones, even when the possibility of detection and punishment is zero--is the goal of moral development. We parents use rules and discipline, of course, to get our children to this stage.

In my book "Brain Rules for Baby: How to Raise a Smart and Happy Child from Zero to 5," I discuss the research-tested strategies that parents can use to aid moral development. At the end of the book, I gather practical tips, including these two:

CAP your rules

Discipline FIRST

Need one more? Read "A Magic Trick for Getting Kids to Follow Rules."

Watch more parenting videos or learn more about your baby's brain at brainrules.net.

Custom-Made Neural Stem Cells

John Medina — Tue, 10 May 2011 04:45:00 +0000

It is ironic that an attempt to do a molecular end-run around a politically hot topic could result in an important breakthrough in the treatment of neurological disease with potentially strong implications for the psychiatric community. Ironic maybe, but true.

In this column, we explore how the judicious use of neural stem cells (NSCs) has led to a research Holy Grail: the creation of research-ready, patient-specific neurons. This technology did not use the famously controversial embryonic stem cells. These custom-made NSCs were created from politically neutral adult tissues (fibroblasts), which were originally isolated from an affected patient. With no embryo in sight, scientists genetically reprogrammed fibroblasts into stem cells, which were then induced to develop into NSCs. This is an extraordinary finding with many topics to be discussed here:

• The potential research utility for patient-specific neurons

• An explanation of how stem cells can be made from adult tissues

• A striking set of results that involve one of the most commonly inherited and lethal childhood neurological disorders: spinal muscular atrophy (SMA)

Research utility for NSCs

Of what possible utility could molecular investigations of a motor disorder have for the mental health community? Before getting into the specifics of the breakthrough, it might be useful to address a real-world psychiatric need, using depression and SSRIs as an example, to see where these data fit.

When we consider the molecular mechanisms of SSRI interactions, it is easy to resort to commonly taught ideas about interactions that involve a single synapse. Nothing could be further from the truth. The most comprehensive neurological view of SSRI interactions must take into account the participation of thousands of individual neurons strung together in coordinated, complex neural networks.

And not just serotonergic neurons. These cells are in contact with many other central nervous denizens, from adjacent glial cells to the extracellular matrix into which the cells are embedded. What do these circuits actually look like in patients who are vulnerable to depression? Is their architecture all that different from patients who do not exhibit this vulnerability? If there are differences, could they eventually predict drug efficacy? Could these differences only be detected by constructing parts of the circuit from scratch, or could they be observed at the level of a single cell?

The first step in answering these questions involves growing a custom-made batch of serotonergic neurons derived only from the affected patients, and then asking relevant structure/function questions. From attempting to understand molecular mechanisms of disease to testing the efficacy of potential medications, such patient-specific test beds would have a powerful research utility. Until recently, the creation of such tailor-made neural substrates had been an impossible goal.

While it will certainly be quite some time before we can grow entire parkinsonian dopaminergic pathways in a dish, it is now possible to create individual patient-specific neurons in culture. The technology comes from that end-run I mentioned earlier, through the use of a certain type of stem cell. It is to these interesting cellular substrates that we now turn.

Inducible stem cells

To say that embryonic stem cell research has been subject to heated political debate is an understatement. The bugaboo has been the source materials from which the stem cells would be isolated—human embryos—many left over from embryos generated in in vitro fertilization laboratories.

In 2006, researchers found a way to create stem cells that bypassed the need for human embryos. The original technique involved the introduction of 4 specific gene products into mature mouse fibroblasts. Surprisingly, this cocktail was found to reprogram adult stem cells and reverse-engineer them into pluripotent stem cells. Like embryonic stem cells, the altered stem cells had the ability to differentiate into any cell type. Eventually, a protocol was developed that did the same thing in human tissues. The cells were called iPSCs, short for induced pluripotent stem cells.

This was quite a breakthrough. No longer would researchers need to harvest cells from extant human embryos to do stem cell research. Skin cells would do. Scientists were soon able to regenerate—and then correct—molecular dysfunction in a mouse model of sickle cell anemia using this technology.

Could any of this work apply to humans, specifically to human neural tissue? Another successful round of experiments (with amyotrophic lateral sclerosis neurons) prompted researchers to study motor disease, ie, SMA.

Of those hereditary neurological disorders capable of causing death in pediatric populations, SMA is easily the most common. The disease is unique to humans and associated with 2 genes, SMN1 and SMN2. For reasons that are not well understood, the absence of the survival motor neuron (SMN) protein results in an alteration of the function of spinal motor neurons. The primary feature is muscle weakness and atrophy. Death occurs at infancy in the most severe forms of the disease, with symptoms generally presenting several weeks after birth. There are many other, nonlethal forms of the disorder, however, with a wide spectrum of symptoms that range from trivial motor effects to catastrophic impairment.

Why this variation? Both genes express in unaffected individuals, but the biological heavy lifting belongs to the SMN1 gene. Because of structural constraints, the expression pattern of the SMN2 gene normally results in only 10% of its protein being processed as a full-length (and functional) polypeptide; 90% of its protein output is truncated (and nonfunctional). That is okay, as long as the SMN1 gene is intact. But when SMN1 is mutated and silent, the disease condition results. Assuming there is a damaged SMN1, the severity of SMA varies according to the number of other SMN2 copies the infant may carry. The more copies of SMN2 gene, the greater the population of functional protein. This interaction explains in part why there can be so much varia-tion in the clinical presentation.

The great mystery is why SMN protein loss results in motor cell alterations that lead to the disease state in the first place. The protein is known to be essential for normal messenger RNA processing and is expressed throughout the body. Yet its absence most severely affects spinal motor neurons.

The most exacting way to attack this “black box” would be to isolate the motor neuron populations from the patient, then compare these populations with unaffected controls and look for differences, of which there are many. These include responses to various medications. It is well known that the application of valproic acid (an anticonvulsant and/or mood stabilizer) or tobramycin(Drug information on tobramycin) (an aminoglycoside) to cultured cells, for example, leads to changes in the expression patterns of both full-length SMN protein and truncated forms. What is the molecular basis of this unusual interaction? And could such differences be used as a “molecular flashlight” to ferret out other secrets regarding the SMN protein? Creating custom-made neurons—one population from an affected individual, another from an unaffected control—would certainly give a test bed capable of answering this question.

The data

Studying these 2 populations is precisely what a group of investigators did. The researchers isolated fibroblasts from an affected child and also from the child’s healthy unaffected mother.

The next step was to generate custom-made neurons. Several steps would be required (Figure). First, using the iPSC protocols I mentioned, the researchers would attempt to create stem cells from both child and parent sources. If that worked, the researchers would then try to induce these patient-derived stem cells into motor neurons—ones that would carry the same biological mechanisms observed in both the diseased and the healthy populations. If successful, the researchers would have their custom-made test beds. They could begin characterization studies; reactions to valproic acid and tobramycin would make obvious first choices to try.

The first step worked. The researchers were able to generate custom-made stem cells from both child and parent. The researchers then tackled the hard part: manufacturing spinal motor neurons from these stem cell populations. They certainly generated promising cellular populations. But the iPSC technolo-gies are new enough that a visual inspection of the generated cells might be necessary—but certainly not sufficient—to show the presence of motor neurons.

There are ways to gain greater reassurance. One way to assay the success of the protocol is to look for bona fide molecular markers of developing spinal neurons. It is known, for example, that extant motor neurons express the protein SMI032 and choline acetyltransferase. Did these induced cells express such proteins? The answer turned out to be yes, both for the affected child and for the unaffected parent. Developing cells in these populations possess transcription factors such as HOXB4, ISLET1, HB9, and OLIG2 as well. Did the induced populations express these markers? They did indeed. While not completely conclusive, it appeared that the researchers had generated patient-specific motor neurons from known affected and unaffected sources.

The next characterization experiments also yielded fruit. They were able to find that the child and parent neurons reacted very differently to the normally stimulating effects of valproic acid and tobramycin. The child’s cells showed elevated levels of SMN protein, both of the truncated form and full-length version. In addition, SMN-containing nuclear structures were altered. No such elevation occurred in the unaffected maternal line of cells.

These differences were significant for 2 reasons. First, it gave the investigators a toehold in their attempts to characterize at a more intimate level the differences between affected and unaffected cells. Second, the differences were discovered as reactions to known medications. The hope is that similar approaches could be used to test the efficacy of various medications before committing to human trials.

Conclusions

These data, full of promising implications as they are, need to be treated with some caution. First, the experimental cells are pure populations derived from stem cells. This hardly reflects the physical in vivo situation. The cells and matrix components that normally surround such cells in nature, including skeletal muscle tissues and even other neurons, are not present in these studies.

Another objection concerns the fidelity of the conversion process itself. The differentiation pattern seen in various molecular markers hinted that the investigators generated real live spinal motor neurons; however, one cannot a priori say they have in every way created a motor neuron that precisely mimics the real-world situation. These cells may lack many subtle molecular processes—and a few extra, equally subtle interactions—that could easily escape detection, at least by current technologies. Because subtle differences can profoundly influence intracellular molecular interactions, especially when we think about reactions to medications, this is a true concern.

The most exciting aspect of these studies comes from what the future holds. A great deal of speculation has gone into thinking about how to tailor medications to individual patients. That certainly is a psychiatric issue . . . I need not talk to this audience about the variable effects of, say, fluoxetine(Drug information on fluoxetine) on clinical outcomes. We have visited this topic in past columns. The ability to create patient-specific cellular test beds may go a long way toward solving some of these problems. Indeed, clinics of the future might routinely screen to decide what medications their patients should receive—and in what concentrations.

There is much work to do. To date, none has been applied to neurological systems relevant to mental health professionals. Even given the cautions mentioned above, there is no reason why it couldn’t. That’s not bad for having to do with an end-run around a hostile, politically charged issue such as stem cell debates. Would that all ethical issues could be decided so cleanly, or with so much fruit.

This article first appeared in Psychiatric Times.

To Sirtuin With Love: Caloric Restrictions and the Genes of the Aging Brain

John Medina — Thu, 07 Apr 2011 23:02:00 +0000

One of the most interesting research efforts of the past few years seems to have taken a page from the preoccupations of the self-help magazine world: the cognitive decline of the brains of aging baby boomers and the obese nature of their grandchildren. These topics have been united by the well-established finding that restricting caloric intake leads to an increased life span in almost every animal tested. Because eating habits are formed early in life, the prediction is that a sensible diet will increase a person’s life span.

Is that true? The link between caloric restriction and life span is certainly solid, although the jury is still out on many of the claims made in the general media. Serious scientists have been studying the molecular biology behind this link for a number of years. One particular group of sequences seems to stand in the gap between aging and food, that of the sirtuin family of genes (also called silent information regulator [SIR] genes). One member of the family, the SIR2 gene, has been studied in particular detail. This article discusses age-related cognitive decline, caloric intake restriction, and the role SIR2 plays in the process.

As the brain ages

It is the canonical experience of people older than 40 that senior moments become an increasingly familiar part of one’s thinking life. We forget names, we forget places, we forget where we put our car keys, and we wonder when—and why—our retrieval systems began to abandon us. Higher-order processing begins to change as well as memory, perhaps not as obviously, but apparently in a far more dramatic way. Although the types of cognitive decline clearly vary from one person to the next, no one escapes these behavioral changes completely or, perhaps, the panic that ensues for some individuals when they compare their previous talent with current abilities.

It is axiomatic that cognitive decline occurs because of physical changes that human brains undergo as they age. Yet demonstrating the specifics of the relationship has not always been easy. With the advent of more sophisticated technologies (and improvements in older technologies), that has begun to change. We now know that changes in the regulation of global gene expression patterns—mostly down-shifting—are observed in a broad swath of the CNS during aging. Gene products specifically involved in the physiological processing of inhibitory signals mediated by γ-aminobutyric acid) have shown particular vulnerability. These neuron-related changes are disproportionately large when compared with changes in other tissues (eg, kidney and muscle tissues show age-related up-regulation).

Alterations in gross neuroanatomical structure have also been observed for many years. Some of the most dramatic involve disruptions of the myelinated fibers that yoke disparate brain regions together to provide specific functions—particularly in the prefrontal cortex (PFC). The changes are generally not due to neuronal loss in the PFC, which is actually quite minimal in most aging brains, but to loss of functional connectivity. The accompanying disruptions of neural integration in these regions of the aging brain result in less organized activity than is found in the brains of youthful controls. Such alterations are thought to be associated with a measurable behavioral change in aging populations: disruption of executive function (a task involved in everything from impulse control to planning for the future). This is part of a general age-related decline in the brain’s higher-order functional abilities.

One of the challenges of studying cognitive decline in elderly populations is separating normal changes in cognition from abnormal pathological changes. Although these are not always easy to distinguish, examination of the aging hippocampus has provided valuable insights. The normal aging pattern of the hippocampus involves an inhibition of metabolic activities of the dentate gyrus and subiculum. That is not what you see in patients who have Alzheimer disease. At least initially, the inhibition primarily targets the entorhinal cortex. Neuronal death in these tissues, with a general volumetric shrinkage of the medial temporal lobe, has been shown to distinguish the disease state from typical aging processes.

It is also a matter of calories

Many of the data presented above appear to describe natural, typical processes. But are they inevitable? One of the first questions many people ask after going a few rounds with their senior moment brains is: can the decline be reversed? These are often the questions asked by people who want to increase their life span. The surprising answer to both questions, in a few cases described below, is yes.

One of the most remarkable discoveries in the field of life span alteration occurred in the past century and has to do with caloric restriction. (This does not mean caloric starvation; malnutrition does not provide the benefit and is a completely different issue.) A controlled decrease in the amount of calories consumed has changed the life span of a surprising variety of animals, including mammals. It truly does mean that if you eat less, you will live longer.

The benefits of caloric restriction have been shown to have brain-specific effects as well. Caloric restriction can alter the regulatory genetic down-shifting phenomenon discussed earlier. It has also been shown to change the age-related neuronal degradation in nonhuman primates. Most relevant to our story, caloric restriction can affect human cognitive functioning. In one remarkable study, a caloric restriction protocol that lasted 90 days dramatically improved the verbal memories of a healthy geriatric cohort. Caloric restriction has even been shown to inhibit amyloid-related plaque formation in transgenic mice models of Alzheimer disease.

A matter of genes

Such robust findings work like scaffolding for researchers interested in the molecular biology behind the aging process and have certainly piqued the interest of people wanting to extend their life spans. What is the molecular mechanism behind the life span–extending properties of feeling hungry all the time? One of the earliest fruits of these research efforts was the isolation and characterization of the SIR genes.

The SIR genes were first isolated and characterized in yeast. They are a highly conserved family of sequences found in animals as diverse as roundworms and humans. One intensely studied member of this family is the SIR2 gene (Figure).

The SIR2 gene product functions as an NAD+-dependent deacetylase. In the presence of NAD+, SIR2 removes acetyl groups from proteins. Histone proteins are a favorite target of SIR2. As you may recall from your undergraduate days, histones are groups of proteins around which DNA molecules wrap themselves, somewhat like popcorn wrapped around string. Histones are deeply involved in regulating gene expression. Adding or subtracting subgroups to histones can profoundly influence the expression patterns of the genes in contact with the molecules.

How does SIR2 fit into the caloric restriction story? It was shown years ago that if you introduce SIR2 into yeast in such a fashion that you overdrive its expression, you can increase the yeast’s life span (measured as the number of times a cell completes a round of replication). If you severely restrict the caloric intake of an unmanipulated yeast, you can do the same thing. If you look for levels of SIR2 protein, you find that starvation has elevated its activity. The association appears to be strong, both by correlation and by direct intervention. The link between SIR2 protein and caloric restriction was first found in insects and then in mammals.

Subsequent research has muddied the waters of this otherwise seemingly tight story, however. Other researchers failed to replicate the results of the initial findings. Questions about various technical aspects that provided the original findings have been raised as well. There appear to be differences between genetic backgrounds in the primary test vehicles, from yeast to mice. These issues have yet to be fully resolved.

Such controversies are the nature of a good research project that, while hardly finished, has reached a certain maturity. These controversies are not deal killers regarding the association between the aging process and what goes in your mouth. The devil, as they say, is in the details. The fact that these issues can be raised at all demonstrates the enormous strides that researchers are making regarding the association between aging and eating—two of the most socially important issues of our time. That the arguments can revolve around deciding how the subtraction of acetyl groups changes the cell cycle simply shows how intimate, and how sophisticated, the progress has become.

This article originally appeared in Psychiatric Times.

References

Andrews-Hanna JR, Snyder AZ, Vincent JL, et al. Disruption of large-scale brain systems in advanced aging. Neuron. 2007;56:924-935.

Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature. 2010;464:529-535.

Haigis, MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging and calorie restriction. Genes Dev. 2006;20:2913-2921.

Welberg L. A long and lean life. Nat Rev Neurosci. 2007;8:494-495.

The Neurobiology of Conscious Intent

John Medina — Fri, 04 Mar 2011 00:49:00 +0000

Perhaps the seminal component of any clinician’s behavioral repertoire is the ability to understand the conscious motivations and intentions of their clients. This article addresses the work of conscious motivations at the neuroanatomical level.

I seldom address the notion of consciousness—let alone motivations—in this column for a very good reason. Nobody really knows what they are or even if there is a “they.” The literature is confusing, but it hasn’t stopped researchers from speculating on possible neuroanatomical and biochemical substrates that undergird the phenomena. Without a broad consensus about what is being studied, there can be no neurons, let alone molecules, for active experimental consideration. After all these years, researchers have yet to isolate an area of the brain solely devoted to the experience of consciousness. There may be none.

Given the importance of these issues to the mental health professions, I revisit the concept of motivations from time to time—but only when the data are conservatively presented, with sober, modest conclusions. The findings described here originate from experiments that have attempted to determine how we voluntarily choose to perform a motor task (action planning). This work requires reviewing background information on association cortices and the neural substrates behind a decision to initiate voluntary action.

Association cortices

Functionally, the cortical regions of the brain and their myriad interlocking circuits can be divided into 3 modules. These consist of front-, back-, and middle-end domains.

• Front-end functional domains are sensory information processing centers. The brain receives input from the eyes, ears, and other sensory systems. It sends the input off to various places for further processing.

• Back-end functional domains involve motor control systems. These systems essentially respond to whatever command the sensory cortices give to it (eg, execute a decision to move).

• The middle-end suite involves nearly everything other than front-end and back-end functional domains. These association cortices generally entail higher processing features and are some of the least understood and the most mysterious parts of the brain.

One such cortex, located in the inferior posterior parietal cortex, is a sensorimotor association region that links sensory stimuli to motor movement. It may even be involved in sensory prediction, which calculates the consequences of a given action through the simultaneous evaluation of input from both sensory (front-end) and motor (back-end) functional domains.

Volitional motor movement

Many of the actions humans initiate on a day-to-day basis seem to depend on a kind of internal free will. This sequence of events (also known as volitional motor movement) gives humans a sense of control: we act because we want to act. That is why researchers use volitional motor movements in their research designs. Researchers interested in volitional behavior study neural prime movers behind decision making.

Exactly what does it mean to want to do something? We do not really know. The events that initiate movement occur in a fairly straightforward sequence (although it depends on the source of the signal). For example, a central processing area with directives for voluntary motor movements pass through a final staging area before the execution of an action. This region is the primary motor cortex.

Research on laboratory animals demonstrates that this cortex decides on a course of action that depends on the source of signals it receives before the execution of that action. One source originates in the premotor cortex. Signals in this area initiate movements in response to a specific external trigger, such as a visual cue.

The second source arises in the presupplementary motor area, which is stimulated when laboratory animals make the same movements mentioned above, but they do not originate from responses to an external source. The movement instead arises spontaneously; a thought is internally generated through intentional actions. There is an observed rapid rise in electrical signals that build up just before the brain executes these actions. This has led to the notion that the presupplementary motor area harbors some kind of readiness potential, a useful function in generating movement (Figure).

In terms of human behavior, complex human brains have many more research issues to solve than standard laboratory animal research can address. One potential confounder is conceptual. With research of this type, scientists often tell subjects to choose (or not to choose) from a variety of options. Is that voluntary? Hardly. This is like saying, “Okay, it’s time to have some voluntary volitional behavior now,” or like runners at a race who respond to the starting gun. Do volitional actions disappear in these experiments with human subjects? Are these subjects simply reacting to commands to respond, not to respond, or to respond however they want? To test volition, researchers should not control the input. Nevertheless the experimenter must, almost by definition.

Wilder Penfield revisited

Another complexity involves engineering. How does conscious intent to move an arm relate to the actual movement of the arm? This could be partially resolved with electrical stimulation mapping in which surgeons create a map of the brain on conscious patients to understand what tissues need to be avoided during certain manipulations (such as resection). No pain neurons exist in the brain. The patient, immobilized in a stereotactic frame, can be consciously interrogated while the surgery takes place. The surgeon applies a gentle electrical current to the open tissue, talks to the patient about what he or she is experiencing, and makes a map that discerns what areas to avoid during cutting. Working primarily with epileptic patients, the legendary Canadian physician Wilder Penfield first performed these techniques.¹

This technique has proved to be of great value in understanding volitional components of motor movement. It was discovered almost 2 decades ago that if one stimulates a specific area of the human presupplemental area, the patient will experience a conscious urge to move.² This gets around the runner’s starting gun problem mentioned previously. An external electrical stimulator supplies a specific quantity of electricity—and a desire to do something is suddenly generated!

As important and well-characterized as these data are, they hardly explain what causes the presupplemental area to generate the signal in subjects not undergoing surgery. Some research findings answer this question and have led to some intriguing results.^3,4

When the inferior posterior parietal cortex was stimulated, the patient experienced an urge to move specific body parts. Stimulating one area caused patients to want to move their arms. Another region, the lips. Another region, the chest. This is similar to what one observes in frontal lobes, except that you are nowhere near the frontal lobes. Recall that this is the associative cortex region (a sensorimotor associative area at that), quite distinct from anything observed in the well-characterized general motor areas of the frontal lobes. Was this simply a remote stimulation?

This result showed that the answer would be no. The parietal cortex urges were qualitatively different from those obtained by stimulating parts of the presupplementary cortex. It is well known that if the presupplementary cortex is stimulated at a low current, the urge to act is acquired. However, if the same region is stimulated at high current, actual movement occurs. That’s not what happened in the parietal cortex. The urge was stimulated at low intensities, but movement was never generated at higher ones. Instead, subjects felt that they had already performed some movement.

This is important. The desire to move did not result from subtle motor contractions that may have been generated by motor regions (an alternative idea that has been put forth as a rational explanation for the results in previous experiments). Parietal stimulation never produces muscle activity, regardless of the intensity. The stimulation of the premotor cortex itself produces large-limb movements in subjects, but never the desire to move the limbs. They usually remain unaware that movement has occurred when these regions are stimulated.

These results suggest the presence of 2 specific aspects of conscious intention (however one defines it). One might be the conscious correlation of preparatory motor commands in the presupplemental cortex region, as is clearly observed in laboratory studies of animals. The other might involve sensory prediction of the consequences of those commands, under the domain of the association cortex region. A portion of conscious intent seems to be a specific class of experiences housed within the parietal lobe.

Conclusions

It appears that the parietal lobe contributes to the conscious experience of intention, at least in regard to motor movement. These results cement 1 more brick onto the great construction project that seeks to define intention. But they hardly hint at the overall building.

Pushing the edge of our understanding into the murky world of association cortex only means that future experiments will be trickier to interpret. Electrical stimulation mapping, as good as it is, is necessarily a blunt instrument that stimulates thousands of neurons simultaneously. Not isolated modules, these regions connect to each other in complex, little-understood ways. That the regions produce different behaviors is an important finding but not a defining one.

How do the frontal and motor aspects of volitional experience differ from the parietal, sensory versions? What factors stimulate the parietal lobes in the first place? What about remote effects?

Questions such as these remain to be answered and are just a few of the many that researchers will face as they attempt to define intentional and conscious experiences.

This article originally appeared in the Psychiatric Times.

References

1. Penfield W, Erickson TC. Epilepsy and cerebral localization: a study of the mechanism, treatment and prevention of epileptic seizures (Review). South Med J. 1942;35:222.
2. Fried I, Katz A, McCarthy G, et al. Functional organization of human supplementary motor cortex studied by electrical stimulation. J Neurosci. 1991;11:3656-3666.
3. Haggard P. Human volition: towards a neuroscience of will. Nat Rev Neurosci. 2008;9:934-946.
4. Custers R, Aarts H. The unconscious will: how the pursuit of goals operates outside of conscious awareness. Science. 2010;329:47-50.

Discipline Advice: A Magic Trick for Getting Kids to Follow Rules

John Medina — Mon, 21 Feb 2011 22:49:00 +0000

Let's say little Aaron has been punished for a moral infraction -- stealing a pencil from classmate Jimmy -- just before a test. The punishment was subtractive in nature -- Aaron would have no dessert that night. But Aaron was not just punished and left alone.

He was also given a magic follow-up sentence, one that makes any form of punishment more effective, long-lasting, and internalized.

Watch this video from brainrules.net to see an example (watch on YouTube):

Explanations given to Aaron ranged from "How could Jimmy possibly complete his test without his pencil?" to "Our family doesn't steal."

Here's what happens to Aaron's behavior when explanations are supplied consistently over the years:

When Aaron thinks about committing that same forbidden act in the future, he will remember the punishment. He becomes more physiologically aroused, generating uncomfortable feelings.

Aaron will make an internal attribution for this uneasiness. Examples might include: "I'd feel awful if Jimmy failed his test," "I wouldn't like it if he did that to me," "I am better than that," and so on. Your child's internal attribution originates from whatever rationale you supplied during the correction.

Now, knowing why he is uneasy -- and wanting to avoid the feeling -- Aaron is free to generalize the lesson to other situations. "I probably shouldn't steal erasers from Jimmy, either." "Maybe I shouldn't steal things, period."

Cue the applause of a million juvenile correction and law-enforcement professionals. Inductive parenting provides a fully adaptable, internalizable moral sensibility -- congruent with inborn instincts. (Aaron also was instructed to write a note of apology, which he did the next day.)

Kids who are punished without explanation do not go through these steps. Parke found that such children only externalize their perceptions, saying, "I will get spanked if I do this again." They were constantly on the lookout for an authority figure; it was the presence of an external credible threat that guided their behavior, not a reasoned response to an internal moral compass. Children who can't get to step two can't get to step three, and they are one step closer to Daniel, the boy who stabbed a classmate in the cheek with a pencil.

The bottom line: Parents who provide clear, consistent boundaries whose reasons for existence are always explained generally produce moral kids.

Note that I said "generally." Inductive discipline, powerful as it is, is not a one-size-fits-all strategy. The temperament of the child turns out to be a major factor. For toddlers possessed of a fearless and impulsive outlook on life, inductive discipline can be too weak. Kids with a more fearful temperament may react catastrophically to the sharp correctives their fearless siblings shrug off. They need to be handled much more gently.

All kids need rules, but every brain is wired differently, so you need to know your kid's emotional landscapes inside and out -- and adapt your discipline strategies accordingly.

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