Looking Schizophrenia in the Eye

272994276_3c83654e97_bMore than a century ago, scientists discovered something usual about how people with schizophrenia move their eyes. The men, psychologist and inventor Raymond Dodge and psychiatrist Allen Diefendorf, were trying out one of Dodge’s inventions: an early incarnation of the modern eye tracker. When they used it on psychiatric patients, they found that most of their subjects with schizophrenia had a funny way of following a moving object with their eyes.

When a healthy person watches a smoothly moving object (say, an airplane crossing the sky), she tracks the plane with a smooth, continuous eye movement to match its displacement. This action is called smooth pursuit. But smooth pursuit isn’t smooth for most patients with schizophrenia. Their eyes often fall behind and they make a series of quick, tiny jerks to catch up or even dart ahead of their target. For the better part of a century, this movement pattern would remain a mystery. But in recent decades, scientific discoveries have led to a better understanding of smooth pursuit eye movements – both in health and in disease.

Scientists now know that smooth pursuit involves a lot more than simply moving your eyes. To illustrate, let’s say a sexy jogger catches your eye on the street. When you first see the runner, your eyes are stationary and his or her image is moving across your retinas at some relatively constant rate. Your visual system (in particular, your visual motion-processing area MT) must first determine this rate. Then your eyes can move to catch up with the target and match its speed. If you do this well, the jogger’s image will no longer be moving relative to your retinas. From your visual system’s perspective, the jogger is running in place and his or her surroundings are moving instead. From both visual cues and signals about your eye movements, your brain can predict where the jogger is headed and keep moving your eyes at just the right speed to keep pace.

Although the smooth pursuit abnormalities in schizophrenia may sound like a movement problem, they appear to reflect a problem with perception. Sensitive visual tests show that motion perception is disrupted in many patients. They can’t tell the difference between the speeds of two objects or integrate complex motion information as well as healthy controls. A functional MRI study helped explain why. The study found that people with schizophrenia activated their motion-processing area MT less than controls while doing motion-processing tasks. The next logical question – why MT doesn’t work as well for patients – remains unanswered for now.

In my last two posts I wrote about how delusions can develop in healthy people who don’t suffer from psychosis. The same is true of not-so-smooth pursuit. In particular, healthy relatives of patients with schizophrenia tend to have jerkier pursuit movements than subjects without a family history of the illness. They are also impaired at some of the same motion-processing tests that stymie patients. This pattern, along with the results of twin studies, suggests that smooth pursuit dysfunction is inherited. Following up on this idea, two studies have compared subjects’ genotypes with the inheritance patterns of smooth pursuit problems within families. While they couldn’t identify exactly which gene was involved (a limitation of the technique), they both tracked the culprit gene to the same genetic neighborhood on the sixth chromosome.

Despite this progress, the tale of smooth pursuit in schizophrenia is more complex than it appears. For one, there’s evidence that smooth pursuit problems differ for patients with different forms of the disorder. Patients with negative symptoms (like social withdrawal or no outward signs of emotion) may have problems with the first step of smooth pursuit: judging the target’s speed and moving their eyes to catch up. Meanwhile, those with more positive symptoms (like delusions or hallucinations) may have more trouble with the second step: predicting the future movement of the target and keeping pace with their eyes.

It’s also unclear exactly how common these problems are among patients; depending on the study, as many as 95% or as few as 12% of patients may have disrupted smooth pursuit. The studies that found the highest rates of smooth pursuit dysfunction in patients also found rates as high as 19% for the problems among healthy controls. These differences may boil down to the details of how the eye movements were measured in the different experiments. Still, the studies all agreed that people with schizophrenia are far more likely to have smooth pursuit problems than healthy controls. What the studies don’t agree on is how specific these problems are to schizophrenia compared with other psychiatric illnesses. Some studies have found smooth pursuit abnormalities in patients with bipolar disorder and major depression as well as in their close relatives; other studies have not.

Despite these messy issues, a group of scientists at the University of Aberdeen in Scotland recently tried to tell whether subjects had schizophrenia based on their eye movements alone. In addition to smooth pursuit, they used two other measures: the subject’s ability to fix her gaze on a stable target and how she looked at pictures of complex scenes. Most patients have trouble holding their eyes still in the presence of distractors and, when shown a meaningful picture, they tend to look at fewer objects or features in the scene.

Taking the results from all three measures into account, the group could distinguish between a new set of patients with schizophrenia and new healthy controls with an accuracy of 87.8%. While this rate is high, keep in mind that the scientists removed real-world messiness by selecting controls without other psychiatric illnesses or close relatives with psychosis. This makes their demonstration a lot less impressive – and a lot less useful in the real world. I don’t think this method will ever become a viable alternative to diagnosing schizophrenia based on their clinical symptoms, but the approach may hold promise in a similar vein: identifying young people who are at risk for developing the illness. Finding these individuals and helping them sooner could truly mean the difference between life and death.

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Photo credit: Travis Nep Smith on Flickr, used via Creative Commons License

Benson PJ, Beedie SA, Shephard E, Giegling I, Rujescu D, & St Clair D (2012). Simple viewing tests can detect eye movement abnormalities that distinguish schizophrenia cases from controls with exceptional accuracy. Biological psychiatry, 72 (9), 716-24 PMID: 22621999

Genetics Post on DoubleXscience

I recently contributed a post to DoubleXScience, a site dedicated to all things women and science. The piece is called Armchair Genetics from Jamestown to Scott Brown and can be found here. It touches on children and race, assumptions, celebrities, a Cheerios ad, and the history of anti-miscegenation laws in the US (particularly relevant in light of the recent rulings on gay marriage). Please feel free to comment and share your own experiences or just let me know what you think!

Remains of the Plague

The history of science is littered with bones. Since antiquity, humans have studied the remains of the dead to understand the living. The practice is as common now as ever; only the methods have changed. In recent years, high-tech analyses of human remains have solved mysteries ranging from our ancestors’ prehistoric mating patterns to the cause of Beethoven’s death. The latest example of this morbid scientific tradition can be found in the e-pages of this month’s PLOS Pathogens. The colorful cast of characters includes European geneticists, a handful of teeth, a 6th century plague, and the US Department of Homeland Security.

Although the word plague is often used as a synonym for disease, plague actually refers to a particular type of illness caused by the bacterium Yersinia pestis. Rampant infection by Y. pestis was responsible for a recent pandemic in the 19th to 20th centuries. Before that it caused the 14th to 17th century pandemic that included the epidemic known as the Black Death.

Yet the pestilence of pestis may have swept across human populations long before the Black Death. According to historical records, a terrible pandemic killed people from Asia to Africa to Europe between the 6th and 8th centuries. It struck the Roman Empire under the watch of Emperor Justinian I, who contracted the disease himself but survived. The pandemic now bears his name: the Justinianic Plague. But was Justinian’s malady really a plague or has history pinned the blame on the wrong bacterium? A group of researchers in Munich decided to find out.

How?

By digging up ancient graves, of course. And helping themselves to some teeth.

The ancient graves were in an Early Medieval cemetery called Aschheim in the German state of Bavaria. The site was a strange choice; the authors reveal in their paper that the historical record shows no evidence that the Justinianic Plague reached Bavaria. However, the site was conveniently located within driving distance of most of the study’s authors. (It’s always easiest to do your gravedigging closer to home.) The authors did have solid evidence that the graves were from the 6th century and that each grave contained two or more bodies (a common burial practice during deadly epidemics). In total, the group dug up 12 graves and collected teeth from 19 bodies.

The scientists took the teeth back to their labs and tested them for a stretch of DNA unique to Y. pestis. Their logic: if the individuals died from infection by Y. pestis, their remains should contain ample DNA from the bacteria. Of course, some of this DNA would have deteriorated over the course of 1.5 millennia. The scientists would have to make do with what they found. They used three different methods to amplify and detect the bacterial DNA, however they only found a reliably large amount of it in the teeth of one individual, a body they affectionately nicknamed A120. They genotyped the Y. pestis DNA found in A120 to see how the bacterial strain compared with other versions of the bacterium (including those that caused the Black Death and the 19th-20th century plague pandemic.) The analysis showed that the Justinianic strain was an evolutionary precursor to the strain that caused the Black Death. Like the strains that sparked the second and third pandemics, this strain bore the genetic hallmarks of Y. pestis from Asia, suggesting that all three plague pandemics spread from the East.

The authors write that they have solved their historical mystery.

“These findings confirm that Y. pestis was the causative agent of the Justinianic Plague and should end the controversy over the etiological agent of the first plague pandemic.”

Ordinarily, the discussion sections of scientific papers are littered with qualifiers and terms like might be and suggestive. Not so here, even though the authors’ conclusion explains a phenomenon that killed many millions of people worldwide based on data from the decomposing remains of a single person who lived in a region that historians haven’t connected with the pandemic. In most branches of science, sweeping conclusions can only be made based on large and meticulously selected samples. In genetics, such rules can be swept aside. It is its own kind of magic. If you know how to read the code of life, you can peer into the distant past and divine real answers based on a handful of ancient teeth.

As it turns out, the study’s result is more than a cool addition to our knowledge of the Early Middle Ages. Plague would make a terrible weapon in the hands of a modern bioterrorist. That’s why the US Department of Homeland Security is listed as one of the funding sources for this study. So the next time you hear about your tax dollars hard at work, think of Bavarian graves, ancient teeth, and poor old A120.

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Photo credit: Dallas Krentzel

ResearchBlogging.org

Harbeck M, Seifert L, Hansch S, Wagner DM, Birdsell D, Parise KL, Wiechmann I, Grupe G, Thomas A, Keim P, Zoller L, Bramanti B, Riehm JM, Scholz HC (2013). Yersinia Pestis DNA from Skeletal Remains from the 6th Century Reveals Insights Into Justiniac Plague PLOS Pathogens DOI: 10.1371/journal.ppat.1003349

Divvying Up Baby

I recently bought my baby new pajamas with a decal that says, “50% Dad + 50% Mom = 100% Me!” I couldn’t resist an outfit that doubles as both math and biology lessons. But on further reflection, I’ve realized that this simple formula is wrong in more ways than one.

To begin with, my baby doesn’t look like she’s 50% Mom. At best, she looks about 10% Mom. I’ve written before about how our daughter would be a mixture of traits from European and Indian peoples, reflecting her mom and dad’s respective heritages. Yet she arrived looking like a wholly Indian baby. This is fine, of course. I think she’s absolutely perfect with her caramel skin and jet black eyes and hair. But it’s hard to keep a straight face when friends politely ask us who we think she resembles. And when I’m out with her in public I’m aware that I look like her nanny, if not someone who’s stolen a baby. She truly doesn’t look like she’s mine.

How else is the formula wrong? Genetically. Sure, our daughter’s nuclear genes are comprised of DNA sequences from both my husband and me. But she has another sort of DNA in her body, one that literally outweighs the conventional type. This DNA lives in her mitochondria, the bacteria-like structures that populate our every cell. Mitochondria are like tiny internal combustion engines, generating all of our energy through respiration and releasing heat that makes us warm-blooded animals. Although mitochondria don’t have many actual genes, they each carry several copies of those genes. Multiply that by the 10 million billion or so mitochondria in our bodies and you’ll find that we each contain more DNA by weight for mitochondria than humans. And these mitochondrial genes are inherited entirely from the mother.

Mitochondrial genes can’t claim credit for your eye color, jaw shape, or intrinsic disposition. Their reach is mostly limited to details of your metabolism and your susceptibility to certain diseases. But mitochondrial DNA is significant for another reason: scientists use it to trace human lineages across the globe. After all, they don’t get reshuffled in each generation as our nuclear genes are. Mitochondrial inheritance can be traced back hundreds of thousands of years, following the maternal lineage at every generation. Unlike the historian’s genealogy, which often follows surnames passed down from fathers, the scientist’s genealogy is a tree built of mothers alone.

So it is through our mothers that our heritages can be traced into the distant past. In every one of her cells, my baby carries a map leading back through me and my mother and her mother and beyond . . . unbroken all the way back to our earliest origins as modern humans. And since my baby is a girl, she can continue that line. So long as she has a daughter and she has a daughter and so on, I will remain a part of that ongoing chain.

My condolences to all you men out there. Same to all you women who only had sons. You’ve passed on your nuclear genes and your child may be the spitting image of you, but your mitochondrial chain has been broken and you will be left out of the biologist’s tree. Although my daughter looks classically Indian, her mitochondrial DNA reveal only her European lineage. Despite the hair, eyes, and skin she inherited from her daddy, my baby’s mitochondria are mine all mine. She and I are links in a traceable chain of human life while my husband is nowhere to be found.

That’s something I can remember the next time I’m mistaken for the nanny.

Halfsies!

My husband spotted another one yesterday. A half-Indian, half-Caucasian blend. The woman had an Indian first and last name, but her features were more typical of a Persian ethnicity than either Indian or white. My husband overheard her describing her heritage and smiled. These days, with a half-Indian, half-white baby on the way, we’re hungry for examples of what our baby might look like. We’ve found a few examples among our acquaintances and some of my husband’s adorable nieces and nephews, not to mention the occasional Indian-Caucasian celebrity like Norah Jones. We think our baby will be beautiful and perfect, of course, although we’re doubtful that she’ll look very much like either one of us.

Many couples and parents-to-be are in the same position we are. In the United States, at least 1 in 7 marriages takes place between people of different races or ethnicities, and that proportion only seems to be increasing. It’s a remarkable statistic, particularly when you consider that interracial marriage was illegal in several states less than 50 years ago. (See the story of Loving Day for details on how these laws were finally overturned.) In keeping with the marriage rates, the number of American mixed race children is skyrocketing as well. It’s common to be, as a friend puts it, a “halfsie.” At least in urban areas like Los Angeles, being mixed race has lost the negative stigma it had decades ago and many young people celebrate their mixed heritages. Their unique combinations of facial and physical features can be worn with pride. But the mixture goes deeper than just the skin and eyes and hair.

At the level of DNA, all modern humans are shockingly similar to one another (and for that matter, to chimpanzees). However, over the hundreds of thousands of years of migrations to different climates and environments, we’ve accumulated a decent number of variant genes. Some of these differences emerged and hung around for no obvious reason, but others stuck because they were adaptive for the new climates and circumstances that different peoples found themselves in. Genes that regulate melanin production and determine skin color are a great example of this; peoples who stayed in Africa or settled in other locations closer to the Equator needed more protection from the sun while those who settled in sites closer to the poles may have benefited from lighter skin to absorb more of the sun’s scarce winter rays and stave off vitamin D deficiency.

In a very real way, the genetic variations endemic to different ethnic groups carry the history of their people and the environments and struggles that they faced. For instance, my husband’s Indian heritage puts him at risk for carrying a gene mutation that causes alpha thalassemia. If a person inherits two copies of this mutation (one from each parent), he or she will either die soon after birth or develop anemia. But inheriting one copy of the gene variant confers a handy benefit – it makes the individual less likely to catch malaria. (The same principle applies for beta thalassemia and sickle cell anemia found in other ethnic populations.) Meanwhile, my European heritage puts me at risk for carrying a genetic mutation linked to cystic fibrosis. Someone who inherits two copies of this gene will develop the debilitating respiratory symptoms of cystic fibrosis, but thanks to a handy molecular trick, those with only one copy may be less susceptible to dying from cholera or typhoid fever. As the theory goes, these potentially lethal mutations persist in their respective populations because they confer a targeted survival advantage.

Compared to babies born to two Indian or two Caucasian parents, our baby has a much lower risk of inheriting alpha thalassemia or cystic fibrosis, respectively, since these diseases require two copies of the mutation. But our child could potentially inherit one copy of each of these mutations, endowing her with some Suberbaby immunity benefits but also putting her children at risk for either disease (depending on the ethnicity of her spouse).

The rise in mixed race children will require changes down the road for genetic screening protocols. It will also challenge preconceived notions about appearance, ethnicity, and disease. But beyond these practical issues, there is something wonderful about this mixing of genetic variants and the many thousands of years of divergent world histories they represent. With the growth in air travel, communication, and the Internet, it’s become a common saying that the world is getting smaller. But Facebook and YouTube are only the beginning. Thanks to interracial marriage, we’ve shrunk the world to the size of a family. And now, in the form of our children’s DNA, it has been squeezed inside the nucleus of the tiny human cell.

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