Zoloft is a popular drug used for the treatment of depression symptoms.

Depression is hardly new. The Roman physician Galen, in the second century A.D., expounded on the prevailing medical view that four bodily fluids, or humors, existed within all people but that the unique variation of these humors within people resulted in individual differences among people in their behavior and temperament. An excess of black bile, for example, indicated a melancholic personality.

Fortunately, a lot of scientific progress has been made since then in understanding depression to be an organic, brain-based medical condition that afflicts millions. In fact, an individual has a ten to fifteen percent lifetime risk of developing a major depressive episode. But as Dr. Karl Deisseroth, a Stanford neuroscientist and psychiatrist, told me during our interview for “Illuminating Depression”, “Diagnosis is a big challenge because in psychiatry, we don’t have a lab test. There’s not a blood draw that you can do as you might to check how your liver is doing or how your thyroid function is doing.” So given that the diagnosis of depression is based on clinical observation (most often done by a primary care physician), one can’t help feel that hard, empirical understanding of depression is somewhat lacking, especially when compared to diseases of other organs like the heart and lungs where tests do exist to gauge the presence of pulmonary and cardiovascular diseases.

This was the most interesting observation for me when working on this story. Imagine a medical disease that afflicts eighteen million people in the U.S. (26 million if you include Bipolar Disorder), for which more than 160 million prescriptions were filled in 2008, that is one of the leading causes of disability in the U.S., but a disease for which no definitive medical model of pathology exists. Increasingly, doctors are prescribing antidepressants to treat not just depression but a host of other medical conditions, including chronic pain and insomnia, some of which can co-occur with depression. Sure, we’ve made strides since the time of Galen’s bodily humors and the Freudian view of misplaced hostility and mourning to explain depression, but in some respects, we’re still in the dark about why some people get depression while others don’t, why some people respond to one treatment and not another, or why one person will suffer from a form of depression that is less or more severe than another person. This lack of clear, empirical understanding comes at an awful price to victims of depression, as they encounter remarks from people that tell them to “snap out of it”, implying that they somehow can control the emotional crumbling and dark ideations that accompany the disease.

The consequence of all this is that it’s incredibly tough to create effective, lasting treatments for the disease if we can’t exactly track how the disease affects not only specific regions of the brain but the activity among individual brain cells in regions that may not have even been known to play an integral role in the disease. My layperson’s view is that treating depression currently is a bit like bringing in a car to the mechanic and telling him to fix it but there’s a catch – the mechanic can’t get under the hood to observe directly what’s wrong with the car. We suspect that the problem is with the engine but good luck with opening it up and peering into its pistons. So the mechanic attempts to work on the engine but indirectly, and whatever repairs are attempted may affect the engine but they may also have unwanted effects on the car’s transmission, muffler, timing belt, etc.

Fortunately, advances in imaging techniques like two-photon microscopy and fMRI are elucidating the activity of the depressed brain, allowing the previously impenetrable forest of billions of neurons to be explored, to see their pathways altered, their branches pruned by the disease. And scientists like Philippe Goldin and Kelly Werner are compiling biomarkers like DNA and brain blood flow activity to see if those biomarkers can help predict if people suffering from anxiety and/or depression will respond more favorably to cognitive behavioral therapy than to mindfulness meditation, for example. Dr. Deisseroth is using genetically engineered, photosensitive proteins implanted into rodents’ brains to control brain activity at the level of individual neurons.

Dr. M. Bret Schneider told me during our interview, “A real cure for depression is gonna involve being able to selectively affect those portions of the brain which don’t function properly in depression… But fathoming the huge number of possibilities in each brain with every brain being a little bit different than every other one, is gonna require individualized solutions and will be a scientific feat.” I suppose that with a disease as complex as depression, where one’s individual genetic makeup can influence the kinds of side effects one may experience with an antidepressant, it’s apropos that the future of treating and eventually curing it will entail personalized medicine. Until then, let’s hope that more people bring psychiatry into the research lab to study illnesses like depression, for it’s only through the methodical rigor of science that we have the best hope for curing depression.

Watch the Illuminating Depression television story online.

This radio story tries to cram a lot into five minutes, so if you don't find what you need here, put a comment on the blog, below and I'll see if I can't provide a lead to more information.

Transcranial magnetic stimulation interested me, in part, because of how non-invasive it is. Dr. Bret Schneider, who offers TMS from his private practice in Portola Valley, was one of several experts to suggest that TMS machines might one day be available for home use. Of course, that's a long way off. TMS is expensive: about $5,000 for an initial round of treatment. It's still much easier and cheaper to simply pop a pill each morning. And researchers are still working out how effective it can be.

Studies show that TMS brings a remission in depression to about a third of patients to try it. Another third experience some improvement, and a final third are unaffected. Dr. Schneider says he sees much better success rates on patients who combine TMS with antidepressant drugs (TMS without drugs, he says, is like "trying to drive a car with no gas.") Finally, the FDA approval covers only one TMS machine on the market, Neurostar, although some physicians use other techniques, off-label.

You can find links to the abstracts of clinical studies performed on TMS and depression through a search at pubmed.com. This meta-analysis compares 30 double-blind studies, covering a total of 1164 patients (606 received TMS, 558 received sham treatments).

But TMS is just one in a class of "brain stimulation" depression treatments — an important fact that didn't make it into the story. Others include vagus nerve stimulation, deep brain stimulation and, of course, electroshock convulsive therapy — which is offered here in the Bay Area at the UCSF Langley Porter Psychiatric Institute to severely depressed patients (as well as, less commonly, people suffering from manic depression and schizophrenia).

Quest TV will cover TMS and other depression treatments in greater depth later this season, so stay tuned. For a sneak peak at some of what you'll find on the show, check out Stanford scientist Karl Deisseroth's groundbreaking work using light-sensitive proteins to stimulate neural circuits — work that could someday help treat not just depression, but other brain diseases as well.

Listen to the Depression Advancements radio report online or check out the slideshow below of Dr. Bret Schneider, a consulting assistant professor at Stanford University and a practicing psychiatrist in Portola Valley, discussing depression and the brain.

Now I'm just about the most rational, science-y person you'll ever meet. But the conversation with my wife had me thinking, what "weird" things do I believe in?

Even I have beliefs I can't explain. I have innumerable superstitions. For example, I always put on my right shoe first so it will bring me good luck for the day. I've had a tarot reading done and yes, I read the daily horoscope from time to time. I find my mind's contradictions amazing. My rational brain doesn't believe that these will bring me more happiness or wealth… no chance. But deep down, I want to believe in the power of a horoscope.

On Friday, March 6th, explore why people believe weird things with a talk by renowned skeptic, Michael Shermer. In Scientific American, he's written about the science behind our need to find patterns and the biological reasons why the brain might cause "paranormal experiences." He'll discuss superstitions, pseudoscience, and paranormal claims . For a preview, check out Michael's video Out of Body Experiences.

Michael Shermer presents "Why People Believe Weird Things", Friday 3/6 7 PM at Ohlone College. Tickets are $10 and can be purchased online. For more info, visit Ohlone College's website.

Though it was McCarthy who persuaded his nine other colleagues at the conference to adopt the term "artificial intelligence" to describe the nascent field, the seeds of artificial intelligence were planted earlier. Alan Turing, who was instrumental in breaking the German's Enigma code during WWII, published a paper in 1950 that laid out what came to be known as the "Turing Test:" if a machine could carry out a conversation with a human in such a sophisticated manner as to trick the human into thinking that he or she was conversing with another human, then the machine would have displayed true "intelligence."

But nearly 60 years later, the world still awaits a machine capable of exhibiting "general A.I.", instead of the "narrow A.I." demonstrated by IBM's chess-playing Deep Blue or Stanford University's Stanley, an autonomous robotic vehicle, or other impressive albeit limited applications of A.I. For example, Deep Blue may be able to beat Gary Kasparov at chess but can it beat a 10 year-old at a game of checkers? The lack of a general A.I. is made even more stark when juxtaposed with Moore's Law, a maxim that goes back to 1965 when Intel founder Gordon Moore postulated that the number of transistors on a computer chip would double roughly every 18 months.

There's even a term – "Singularity" – that is being used to describe the moment when technological progress will leapfrog and herald the creation of computers that not only achieve human-like intelligence, but also give rise to a progeny of computers who will be smarter then their digital forbears. Though he didn't coin the term (sci-fi writer Vernor Vinge did), the most famous exponent of this belief is inventor Ray Kurzweil. He places the Singularity as occurring sometime before 2050 and believes that with the advent of this unheralded technological progress, mankind may solve some of our society's most pressing ills, such as global warming, and even conquer death, by uploading one's consciousness into a virtual medium.

Though this seems a far stretch from engineering a domestic robot like Stanford's Artificial Intelligence Robot, top A.I. researchers like Stanford's Andrew Ng and Daphne Koller do believe that computing systems will some day be as smart or smarter than humans. When I spoke with Dharmendra Modha about his work into cognitive computing at IBM, he talked effusively about creating an "i-Brain," a digital accessory that people could carry around, making decisions and processing information like its human cousin. But if you're like me, and lament those moments when you've misplaced your keys or other instances of poor neural performance, you can't help but think that such a device can't arrive soon enough. On second thought, I'll wait until v2.0 hits the shelves.

Watch the Artificial Intelligence: Thinking Big television story report online.

And don't miss our Web Extra: A Dose of A.I. In this QUEST web exclusive, Stanford University computer science professor and artificial intelligence (A.I.) researcher Daphne Koller provides an elegant explanation of how A.I. can be employed in the examining room to diagnose a patient's illness more accurately than a human clinician. Find out more and learn how medical diagnosis is just the tip of the iceberg when it comes to tasks that rely on making sense of a sea of data to arrive at an informed conclusion.

This is the second of two stories born out of an afternoon at UCSF's Memory and Aging Center, where a team of scientists, led by Dr. Bruce Miller, is trying to tease out the differences between as many as 200 dementias that affect aging brains.

The two stories have a lot in common: Both introduce us to people who have lived with extremely difficult degenerative diseases: ALS in "Decoding the Emotional Brain," and frontotemporal dementia in this week's story. Both open up provocative questions about human nature. And neither would have happened without the generosity of a Northern California family – in this case, Cassandra Shafer, who drove down from Forestville with her daughter, Columbia, to tell me about Cassandra's husband and Columbia's father, Keith Jordan.

In these video clips, you meet Keith Jordan in the second half of his disease, after doctors at UC Davis and UCSF diagnosed him with frontotemporal dementia. The videos were taken at UCSF over the course of many hours doctors spent studying Keith and his symptoms. In them, we glimpse of two of Keith's FTD-caused obsessions: joke telling and music. (We also see one of the first symptoms to have emerged: his Jerry Garcia hairdo.)

At first glance, Keith's behavior might strike you as more eccentric than brain-damaged, which is precisely why FTD can take so long to diagnose. If you're a doctor with a 15-minute appointment slot, frontotemporal dementia might just look like a midlife crisis. What we don't see in the video clips are the five heartbreaking years that Cassandra spent trying to figure out what was happening to her husband – a search that included marriage and career counseling, the full gamut of conventional western specialists, yoga, meditation, chelation therapy, replacing every household cleaning product, every pot and pan, all the way to shamanic soul retrieval and exorcism – all while his behavior grew more erratic and difficult to be around. It's impossible to overstate the drain – both emotional and financial — that this search brought on Keith's family.

Keith died in May and Cassandra is still, she says, "inching her way" out of the "foreign land" that FTD plunged her into. As unlikely as it sounds, I think she takes some comfort in the fact that Keith's illness also gave doctors a chance to explore profound questions about human nature and the extent to which the structure of our brains determines who we are.

FTD can turn Democrats into Republicans, and vice versa. People with no interest in art begin to paint obsessively. As the neurons in Keith's right frontotemporal lobe (just behind the right eyebrow) died, his taste in music, his sense of humor, his relationships with his family members and friends changed completely. Our self, in other words, may owe much more to the way our brains are built than we'd care to acknowledge.

And what to make of the fact that this same part of the brain that shapes personality is also responsible for reading other people's reactions? People with some forms of FTD can't empathize with others (hear more about this in our slide show about FTD and art) or read the emotion on another person's face. Not only do they experience radical personality changes, but they lose the ability to sense others' reactions to them. In other words, how we define ourselves – whether we consider ourselves funny, smart, ambitious — seems to have everything to do with how others define us. We are all, in other words, people people.

Which begs the question: What about people raised in isolation, without the critical feedback loop of social interaction? What does FTD tell us, for example, about children who have been deeply neglected in orphanages? Or – taking another angle entirely — autistic people, who have trouble empathizing with others? What does self-perception look like in those who can’t perceive those around them?

If all this is giving you a headache, you might spend some time exploring the web extras we've produced for these two stories. Here, Bruce Miller explains why frontotemporal dementia can bring with it an artistic renaissance. And here, we introduce you to Matt Cheney and find out what his compulsive laughing and crying jags might reveal about emotion and the human brain.

Then use our blog, below, to let us know what you think.

Listen to the Beyond Alzheimer's radio report online, and watch our Web Extra: Dementia and Artistic Renaissance slideshow.

You read that right. In a new study out in Nature Neuroscience, scientists tinkered with a single gene in a mouse and made it less likely to get fat. Finally I can eat as many Double Stufs as I want without worrying about gaining weight. If scientists can turn what they've learned into a pill, that is.

How'd the researchers do it? By changing one part of the mouse's brain, the hypothalamus. One of the hypothalamus' many jobs is body weight regulation. So it was a logical place to start.

The scientists couldn't go in with a wrecking ball and tear the hypothalamus apart. It is an important part of the brain with lots of different duties. They needed to something pretty subtle so the mice would survive but be thinner.

What they did was to keep certain cells in the hypothalamus from being able to release a neurotransmitter called GABA. This was enough to make a mouse better able to maintain a lower weight.

This study suggests that GABA's normal job in the hypothalamus is to keep mice (and probably us) from burning too much energy. Makes sense in the wild. But is quite a pain in my cubicle.

Now, we can't go changing human genes (at least not yet). But perhaps scientists can come up with a pill that will do the same thing. A pill that keeps AgRP neurons from releasing GABA in the hypothalamus.

This is as hard as it sounds. But now that scientists know what to do, pharmaceutical companies will be able to apply all of their firepower to solving this problem. Given the potential market, if anyone can find a medicine for restricting weight gain using this finding, they will.

Before I get too excited, though, I want to see what happens to these mice as they age. Burning calories makes free radicals which damages DNA which causes aging and can cause cancer. Perhaps burning more calories this way might generate more free radicals.

Of course even if it does, maybe we could just take the pills with cranberries or some other anti-oxidant. Or maybe Nabisco can make an Oreo laced with antioxidants…

Being a neurologist in the era of fMRI scanners must feel like being a kid in a candy shop. What's going in there while we're, say, shopping? How about reading? Watching campaign ads? Now that we have a way to take real-time images of the brain at work, the scientific possibilities are endless.

On the surface, the experiment at the heart of this story might seem pretty narrow. It focuses on a rare disorder called pseudobulbar affect, which afflicts only people with ALS, or Lou Gehrig's disease — a far cry from the universal rites of shopping or reading. But what’s fascinating about pseudobulbar is the light it might shed on all of us, and one of the most primal and mysterious human experiences of all: emotion.

People with pseudobulbar get happy and sad, just like the rest of us. They laugh and cry like the rest of us too. But then sometimes, something else happens: They keep going. And going. In this video, you can see how what looks like a laughing fit morphs into something else entirely. It’s as if the laughing and crying mechanisms have become detached from whatever part of the brain triggered the emotion in the first place. Maybe – and this is the hope of scientists Howard Rosen and Robert Levenson – by seeing that disconnect take place in real time through the fMRI, we’ll understand, for the first time, how emotion plays out in people without pseudobulbar affect.

(And it doesn’t stop there. Listen to the radio piece to hear Rosen's theory about what PBA might mean for depression, obsessive compulsive disorder, and, particularly, PTSD.)

Finally, a note about Matt Chaney. As Rosen and Levenson remarked many times, science can't happen without people like Chaney. While the rest of us sat comfortably in front of the fMRI monitors, Chaney spent an hour and a half lying in the cramped quarters of an MRI tube, watching highly emotional videos designed to make him sad. Moving his head by a millimeter would blur the image, so not only is Chaney being taken on an emotional roller coaster, he's doing it without moving a muscle – a lot to ask from anyone, let alone someone with a degenerative muscular disease like ALS.

Journalism is a little less demanding (at least I hope so) but Chaney added to an already long day by spending time in an interview with me. He and his wife, Liz, were also extremely generous in allowing us to share videos of them, which illustrate pseudobulbar far more movingly and effectively than anything I could have written.

Listen to the Decoding the Emotional Brain radio report online, and watch our Web Extra: Emotions from the Inside and Out video.

A look into the science of skin.

In an article this week in the New York Times, brainpower was correlated with the complexity of nerve synapses. Leading researcher Dr. Grant, who has studied the interconnectedness of neurons, likened this connection to technology; "From the evolutionary perspective, the big brains of vertebrates not only have more synapses and neurons, but each of these synapses is more powerful – vertebrates have big Internets with big computers and invertebrates have small Internets with small computers." The brain has been made analogous to a computer before in order to study evolutionary adaptation. However, the brain was not the organ being studied, rather it was human skin.

Have you ever wondered why we have hair only on the tops of our heads and the rest of our skin is relatively bare? Why does our skin come in so many pigmentations? And why does our skin sweat? Dr. Nina Jablonski kept asking why and attributes these adaptations to the need to keep our brain cool. I first heard Dr. Nina Jablonski speak about her most recent book, Skin: A Natural History, in early 2007. I was absolutely enthralled and two hours raced by as she articulated her fascination with skin. Dr. Jablonski divulged into why our skin appears and acts the way it does from an evolutionary standpoint. Her findings showed that about two million years ago our ancestors were running long distances in Africa under the heat of the equatorial sun. To keep their brains cool, sweat glands became more prominent. This in turn let brain size expand and evolve. In the fossil record, it shows after this increase in brain size, Homo sapiens left Africa to migrate into Mainland China.

Skin:A Natural History

So skin was an evolutionary adaptation to keep our large brains cool and working effectively. Skin color, Dr. Jablonski surmised, was what regulated our body's reaction to the sun and its rays. Dark skin evolved to protect the body of those of our ancestors close to the equator. Those ancestors further away evolved light skin in order to take in Vitamin D in less sunny climates. After her talk about Rosacea, which is a condition of constant blushing found in Eastern European nationalities, I asked Dr. Jablonski why. She told me this might have been attributed to ancestors of light skin being overly bundled and getting over-heated. It might have been an adaptation to release heat and cool the brain from the only exposed skin.

In her lecture, Dr. Jablonski did not stop with touching upon evolutionary adaptations, she also delved into how we associate and identify through our skin. We decorate our skin, clothe it, paint it, tattoo it, scar and pierce it. She elucidated skin as an intimate connection with the world as well as our presentation of individuality. Skin: A Natural History and Dr. Nina Jablonski have gained national recognition. She was even invited as a guest on the Colbert Report to talk about her findings. It is rumored that she is following up Skin with more in-depth research. Until then, this is an outstanding look at a very under-appreciated organ, one that might have made the complex nuances of our brain and its synapses possible.

Watch Dr. Nina Jablonski on The Colbert Report: