Thursday, August 27, 2009

More Cool Stuff

Yesterday, I described a conference session I attended this year in which Daniel Weinberger of the NIMH was the presenter and 2000 Nobel Laureate Arvid Carlsson was in the audience. The focus of the piece was that neither brain science nor psychiatry was ever the same following Dr Carlsson's discovery of dopamine. This blog post zooms in on the similarly seismic effects of a study that Dr Weinberger participated in:

I first ran across Dr Weinberger (pictured here) at the 2003 APA in San Francisco, in relation to a gene that influences a different neurotransmitter, serotonin. I was an innocent, about to have my eyes opened:

Dr Weinberger told his audience about a study that came out of his lab, published in Science the year before (Ahmad Hariri, lead author). In the study, the researchers rounded up healthy subjects and put them into a brain scan machine (not all at the same time, I presume. I think they lined them up one at a time). The individuals were divided into two groups, those who had a certain variation to a particular gene, what they call the short allele to the serotonin transporter gene, and those who had the long allele.

The serotonin transporter - or serotonin reuptake pump - is the target of SSRI antidepressants. Based on this knowledge, researchers knew there had to be a genetic smoking gun somewhere, but they were stumped. The problem was they were looking for a "depression gene" or a "bipolar gene." Genes, unfortunately, don't conform to the way we classify psychiatric disorders.

In 1998, for instance, a German team came to the conclusion that "no association between alleles conveying functional differences in serotonin transport gene expression and major depressive disorder or bipolar disorder could be found."

Basically, genes act as "on-off" switches. But they don't switch on "depression" or "bipolar" or anything else. Instead, they activate proteins that regulate how cells function and and organize themselves into interacting with other cells. This in turn may influence whether a certain individual is predisposed to depression or bipolar, but you're not going to find that out by looking for a direct link.

It's simple mechanics really. First link the gene to the cellular function it influences. Dr Weinberger and his team already knew that a certain region of the genome, SLC6A4 with the chromosomal address of 17q21, is responsible for the cellular activity that involves vacuuming excess serotonin from the synapse between the neurons.

But then what? What was the connection to behavior? On one hand, Dr Weinberger and his colleagues needed to build on the work of Dr Carlsson's generation; on the other, they needed to throw away all their preconceptions.

As the study subjects' brains were being scanned, they were made to perform a simple cognitive task involving looking at images of "scary" faces. If you have any doubts about what a two-dimensional image can do to the brain, simply turn on Fox News without the sound. Seriously, just the sight of those idiots - don't get me started.

It turned out that the "short allele" people - that is, those with a certain variation to the gene in question - in reaction to the scary faces, a certain portion of their brains lit up like a Christmas tree. You guessed it, we're talking about the amygdala, which features mightily in my adventures with raccoons and skunks.

As we know, the amygdala mediates fear and arousal, and is directly and indirectly wired into all areas of the brain. Think of the amygdala as a simple smoke alarm. It can detect smoke, but it's too dumb to know whether the smoke is related to grilled meat or a five-alarm fire. The thinking areas of the brain will eventually provide you with the info you need to make a rational decision, but all that takes too way long to boot up.

In the meantime, it's prudent to sound the alarm, even if it is a false alarm. But what if the alarm is over-sensitive or won't shut off? It's one thing for your fight or flight response to kick in at the sight of a predator (or Dick Cheney with a face lift) at the door, but what if you keep having the same reaction to, say, the UPS guy?

When the amygdala goes off, we are reacting rather than thinking. We are operating out of fear. As Dr Weinberger explained to his audience, "this could be the first study to link genes to emotions."

What does this mean? Let's turn to a closely related study:

About 35 years ago, researchers from the University of Otago recruited a "birth cohort" of more than 1,000 infants born in Dunedin, New Zealand, and subsequently assessed them every two or so years. Had my daughter (who was born in Dunedin) arrived five years earlier, she might have been part of that cohort. Then again, had she been born five years earlier, I wouldn't have been the father.

"Longitudinal" studies of this sort represent the gold standard of population research, as opposed to "retrospective" findings based on recalled events. Over the years, this cohort has been to medical and psychiatric and behavioral research what wild Tanzanian chimps have been to Jane Goodall.

On July 18, 2003, the journal Science published the latest installment coming out of Dunedin. The year before, the same research team had identified certain childhood risk factors in antisocial behavior, together with a strong link to a suspect gene (acting on the enzyme MAO-A). This time, the researchers (Avshalom Caspi, lead author) analyzed the cohort for stressful events over the past five years, such as death in the family, losing a job, or breakup with a partner and this time their attention was directed at the very same gene that featured in Dr Weinberger's study.

Lo and behold, of those meeting the criteria for at least four recent stressful events, 43 percent of the short allele people experienced depression vs just 17 percent with the long allele.

In a field where researchers are accustomed to teasing out frustratingly small statistical blips, these numbers represent something truly seismic.

It is important to note that the researchers did not identify this variation as a "depression gene." Rather, drawing the short genetic straw makes one susceptible to stress and its downstream effects (which may include depression). One also needs to have regard for the fact that not all depressions are caused by stress.

Think of the short allele as a "vulnerability gene." Those with the long allele, by contrast, may be regarded as the proud owners of a "resilience gene."

To further clarify the resilience factor, the depression rates for those with the long allele did not vary, regardless of whether they had experienced zero recent stressful events or four or more. Those with the short allele, by contrast, only experienced this same low depression rate as the long allele people when not exposed to any major stress, period.

As Dr Weinberger described it at a subsequent APA, this particular gene "impacts on how threatening the environment feels." Or, as his colleague Andreas Meyer-Lindenberg put it at yet another conference I attended, the short allele "impairs your ability to respond to what life throws at you."

Noted the Dec 19, 2003 Science: "Together, these studies suggest that the gene variant biases people to perceive the world as highly menacing, which amplifies life stresses to the point of inducing depression."

Science was reporting on what it considered the top ten scientific breakthroughs of the year. This pair of findings (plus several others) ranked number two. The origin of the universe came in first, and we’re not about to argue with that.

So it's not nature vs nurture. It's more like nature via nurture. But it's even more dynamic than that. The brain isn't simply influencing how we perceive and respond to our environment; our environment, in turn, is literally building our brain. We're not stuck with the same brain cells we were born with. Your brain is literally changing right now, as you are reading this. You might not be able to trade in your hair-trigger amygdala for one a bit less sensitive, but you can literally set to work building your own neuronal work-arounds.

The upshot of all this is that literally every idea about how we think and feel and behave is now in play. Dogma may be dead, but wisdom and insight are thriving. If you're big on biological psychiatry, the brain studies are coming in thick and fast. Likewise, based on precisely these same studies, you can make a case for bringing back Freud. Similarly, if you're bullish on the precepts of the ancients, you can brandish the exact same evidence.

The same applies to centuries-old philosophical foodfights involving the distinction (if any) between the mind and the brain.

Eventually, new findings will resolve a lot of these debates, but in turn the facts are bound to raise a lot more questions than they answer. In the meantime, that strange interlude we call life is demanding we make choices right now.


William Wren said...

thanks for the post

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