Autism, SHANK, and busy highways

Two autism studies in the news. I’ve summarized them at the Thinking Person’s Guide to Autism here. Let’s just say that the headlines, stories, and news releases have hyped yet again. Indeed, the title of this post should’ve been: “Headlines hype, news releases overpromise again in autism research.”

The worst offender is easily, “Proximity to freeways increases autism risk, study finds.” Um, no. The study found that autism rates are higher among people living within 309 meters of freeways. That in no way means that living close to a freeway increases autism risk. It’s a common, basic overinterpretation of correlation and epidemiological conclusions, but it’s really starting to get old. You can read more about the fuzzy definition of “freeway” and “major road” here.

MRI, brain differences, and autism

MRI: Sagittal view of the brain. Photo courtesy of Wikipedia commons.

You may have read the news reports blaring the finding of an “autism test” that could lead to early and definitive diagnosis of autism. The new evaluation, which has proved worthy of its own name, the Lange-Lainhart test, uses magnetic resonance imaging (MRI) techniques to image brain areas to detect changes associated with autism.

I’ve been unable to find the complete paper, reported to have been published in Autism Research on Nov. 29; the journal has only papers through October available on its Website as of this writing. According to reports, however, the authors state that the new test was 94% accurate in identifying who was autistic and who wasn’t among 60 males tested. The participants in the study were ages  8 to 26; 30 were diagnosed with what the researchers call “high-functioning autism,” and 30 were typically developing.

The imaging technique the authors used involves tracing water diffusion along axons, the long connectors that link neurons to other neurons or tissues. This diffusion tensor imaging process yields an image that can highlight variations in the patterns of these connective pathways in different areas of the brain. This study focused on six brain areas associated with language, social, and emotional functioning, all of which are traditionally considered to be problematic among people with autism.

In the brains of non-autistic participants, the flow patterns were organized in a typical way that indicated connectivity among the brain regions. In the participants diagnosed with high-functioning autism, the flow was disorganized in a pattern common to the autistic group, indicating less connectivity and interaction and thus less exchange of information in the network. The researchers repeated the test on another, smaller set of participants, 12 with autism and 7 without, and produced similar results.

These findings imply that autistic brains may operate like a set of computer hardware components that cannot communicate very well with each other while still functioning perfectly well separately. There may be camera that captures a visual image without trouble or a microphone that captures a voice clearly, but the system lacks the network necessary to integrate the two inputs into a unified perception.

The news reports I’ve read on the study make a big deal out the prospect that this imaging breakthrough could lead to earlier diagnosis of autism, something that most experts believe is key to ameliorating some of its negative manifestations. But experts also urge the standard cautious optimism, and rightfully so.

For one thing, the participants in this study were ages 8 to 26, not within the time frame for early diagnosis of autism, and all of them were male. The study findings can’t tell us whether their brains present with these differences as a result of developing with autism, or whether they have autism because their brains are built this way. Before there can be talk of “early diagnosis” and linking these changes to manifestations of autism, we’d need studies showing these differences in much younger children. Further, given the frequent findings of differences between males and females on the spectrum, investigations involving autistic girls and women are necessary.

This study is not the first to use imaging to identify distinctions between autistic and non-autistic people. Other studies have also done so, finding pattern variations in the neuronal tracts of children with autism compared to children without it, in critical areas relevant to the clinical symptoms of autism.

While I find these results intriguing, I note one thing that no one seems to have commented on. In the reports I’ve read about this study, the researchers observe that currently, the only way to diagnose autism is based on a symptom checklist, questionnaires, screenings, and so on—any autism parents reading this will know that drill—and the ultimate call relies on the expertise of the medical professional conducting the evaluations. The implication of these comments is that we need some better, more unequivocal, less-subjective methods of identifying autistic people.

Yet, presumably the autistic boys and men they used for this study were diagnosed using just such subjective evaluation, and their autism diagnoses appear to have been confirmed in 94% of cases by similarities of MRI findings. In my mind, this outcome suggests that the process of subjective evaluation seems to be working pretty well. Of course, we’re a visual species and like our decisions to be given literally in black and white. Such MRI results may fulfill a need that has less to do with correct outcomes than it does with a dose of visual confirmation–and satisfaction.

Bisphenol A: multisystem effects

These bottles were produced without BPA in response to concerns about the chemical. Photo via Creative Commons, attributed to Alicia Vorhees, thesoftlanding

Are endocrine disruptors stealing our future?

Endocrine-disrupting compounds are chemicals in the environment—usually compounds that we have introduced—that can alter normal hormone signaling processes. Often, exposure to these compounds has little immediate effect in adult animals, but it can have big effects on organisms during sensitive developmental periods, like embryogenesis. During embryonic development in vertebrates, steroid hormones govern many processes, and the fetal hormone environment is usually carefully calibrated to ensure that these processes go forward normally.

Tiny amounts, big changes

But many compounds disrupt these processes, knocking them off track and resulting in development that is unusual or abnormal. For example, male alligators exposed in the egg to these compounds—which often persist in fatty tissues or yolk—emerge with serious penile abnormalities that can affect their ability to reproduce. The banned pesticide DDT is probably one of the best-known of these compounds, and exposure to it or its metabolites has been shown to disrupt hormone signaling to the point of altering sex development completely.

When we think of hormones, we often think of puberty, the time when hormones seem to govern our every move. When we think of estrogen, we probably think “female” because estrogen has historically been considered the “female” hormone. What you might not know is that estrogen, which is made in the ovaries, is also made in our brains during embryonic development. In mammals, appropriate male development appears to require neural estrogen synthesis. When estrogen synthesis in embryonic mammals is blocked, the males that develop do not exhibit typical male behaviors when they reach reproductive maturity.

Bisphenol A: ubiquitous chemical

Among the compounds that have been identified as endocrine disruptors is bisphenol A (BPA). In the United States, we produce about 2 billion pounds of BPA a year. Previous studies have demonstrated that BPA can disrupt thyroid signaling to the point of affecting the thyroid’s role in appropriate brain development. In addition, BPA has been linked to feminization of reptiles. Some scientists were aware of BPA’s hormone-activity potential as far back as the early twentieth century.

But because no one took that knowledge or its potential seriously—the field of endocrine disruptors is relatively young—BPA has found its way into almost every aspect of our lives. It is in the dental sealants we put on our teeth to keep the cavities at bay. It is in the lining that coats the insides of food cans to keep the metal from rusting. It is in the hard plastic that we use for baby bottles and teething rings. And it can leach from these products into the food that we eat. BPA is found at high levels in some pregnant women, and it appears to accumulate in higher concentrations around the umbilical cord and in the fetal amniotic fluid.

BPA and effects on the developing brain

Work from Yale and from researchers in Japan also points to some potentially serious effects on the brain. Part of the role of estrogen in brain development is facilitating synaptic connections in a crucial brain area called the hippocampus. The hippocampus is the center where neurons organize that will later be activated to produce sex-appropriate activity in vertebrates. It is also the area of the brain involved in the formation and retention of memory.

The researchers found that small doses of BPA—doses that fall within EPA-approved levels for exposure—can inhibit hippocampal synaptic formation in rats, counteracting the effect of estrogen. That BPA is an estrogen inhibitor could be serious for our brains if the results translate into human effects. As we age and our endogenous estrogen levels decrease, for example, the hippocampus suffers and our memory does, too. If BPA sets this process in motion even earlier, hippocampal—and thus, memory—decline may occur even earlier.

Rodents, monkeys, and people–oh, my

A recent report in Environmental Health Perspectives concludes that rodents, rhesus monkeys, and people all exhibit similar pharmacokinetics with BPA and that exposures may be far greater than previously calculated. Other recent studies suggest effects on sugar metabolism related to diabetes, an association with polycystic ovarian syndrome in rats, and a relationship to the development of asthma in a mouse model.

A drug for Fragile X syndrome?

Hopeful news but not peer-reviewed

A new report describes success in a very small trial with a new drug that targets behavioral signs of Fragile X syndrome. This syndrome, which affects about one in every five thousand children, mostly boys, usually involves some form of intellectual disability along with a suite of typical physical characteristics, including large jaws and ears and elongated faces. It is the most common known heritable cause of intellectual disability and has also been associated with autism.

Novartis has been working on an experimental drug targeting some of the behavioral manifestations of Fragile X and has just reported, via interview, positive results from a small trial. Because the results are not public and have not been peer reviewed, the nature of the improvements is unknown, as is the nature of the drug itself. All that is known is that a parameter in the treatment group improved in some, but not all, participants with Fragile X. Also, the drug targets reduction of the synaptic noise that people with Fragile X experience. This reduction in neural background noise, it is thought, may pave the way for more typical neurological development.

Why is the X fragile?

The X chromosome consists of many many genes. Some of these sequences may contain repeats of the same three nucleotides, or letters of the DNA alphabet. For example, a gene section might have 50 repeats of the sequence C-A-G. These trinucleotide repeats, as they are known, are associated with a few well-known disease states when they occur in larger numbers. At a certain low number of repeats, they may have no effect, but when the number of repeats increases, a phenomenon known as trinucleotide expansion, the result can be disease. Huntington’s disease is one well-known disorder associated with trinucleotide expansion, and the general rule is that the more repeats there are, the more severe and/or the earlier the onset of the disorder.

On the X chromosome, where these repeats achieve sufficient numbers to result in Fragile X syndrome, the X chromosome itself looks like it’s literally at a breaking point. This visual fragility is what gave the disorder its name when this chromosome characteristic was discovered in 1969. A parent who carries an X chromosome with relatively few repeats does not have Fragile X, but the gene is in a state known as a premutation. Thanks to various rearrangements and events during cell division, this premutation can expand even in a single generation to sufficient numbers of repeats to cause the disorder in an offspring.

Because the relevant gene is on the X chromosome, Fragile X is an X-linked disorder. It’s more prevalent among males than among females because males receive only one X chromosome. Without the second X chromosome backup that females have, males are stuck with whatever genes–and mutations–are present on the single X chromosome they receive.

What is the autism link?

Fragile X underlies a small percentage of diagnosed cases of autism, between 2 and 6%. Because of the usual genetic complexity underlying autism, Fragile X is also the most common known single-gene cause of autism.

These prematurely reported results have also yielded some speculation that a drug that is effective in reducing background noise and improving behaviors for people with Fragile X might do the same for autistic people, even if their autism isn’t related to Fragile X. With nothing in the way of peer-reviewed findings to consider and results available only via interview, such hopes remain in the purely speculative realm.

For your consideration

Males are born with a single X chromosome. Females have two. The X chromosome has hundreds of genes on it. How is it that women can walk around with a double dose of these genes, or conversely, men can be healthy with a half dose?

Trinucleotide expansion occurs when a trinucleotide repeat sequence expands in numbers of repeats, potentially evolving from a premutation to a full-blown disruption of a gene. What are some possible mechanisms by which this expansion might occur?

In the article related to this report, there is reference to “synaptic noise” and to the idea that a drug might reduce this noise and allow more space for typical development. What do you think “synaptic noise” is, physiologically, and how might a drug target this noise?

Autism and oxytocin: facilitating social interaction?

Oxytocin: Hormonal bliss

Oxytocin is a peptide hormone the brain produces in the posterior pituitary. It appears to play many roles in our lives, starting with birth, when it manifests one of the few examples of positive feedback during labor: The more you make, the more you make, until the uterus, the most powerful muscle in the body, contracts sufficiently and frequently enough to push a baby out of an area through which you’d think no baby could fit. In fact, in many childbirths, a synthetic form of oxytocin is used to facilitate labor. Following the birth experience, oxytocin works further magic by facilitating the mother-child bond.

Oxytocin doesn’t stop there, however. It also appears to function in facilitating trust among adults. One study found that a whiff of the hormone caused study participants to be more likely to continue in their trusting behavior, even if the target of their trust had betrayed them.

Social deficits characterize autism

Autism is a term that describes a broad spectrum of developmental manifestations that can include problems with verbal communication, social interaction, and motor skills. Some research has indicated that people with autism may have comparatively low levels of oxytocin, which has led to the hypothesis that boosting these levels might facilitate a greater social understanding for them.

Oxytocin boosts social skills?

A recent study from France published in the Proceedings of the National Academy of Sciences appears to bear out this idea. Caveats include the fact that while it was a controlled clinical trial, the study involved only 13 autistic people who had been diagnosed either with high-functioning autism (HFA) or Asperger’s (and 13 age-matched non-autistic participants). The low number of participants and the mix of diagnoses (there is controversy about the overlap or equivalency of HFA vs. Asperger’s) mean that these findings qualify as suggestive only. In addition, the authors in their paper offer some assumptions about autism that do not necessarily apply or apply in equal measure among all autistic people.

With those caveats in mind, the study findings remain intriguing. The autistic participants exhibited a greater awareness of social dynamics after exposure to oxytocin, in addition to also having higher measured levels of the hormone in their blood. Oxytocin, like most hormones, does not persist for long, and these effects would be expected to be only transient.

Is it direct improvement of social function or diminished social anxiety?

Among the assumptions the paper authors make about autism, one is that autistic people do not engage in eye contact and that this indicates a lack of social engagement. Another assumption is that the autistic participants were unable to understand the social dynamics without oxytocin because of a social incapacity.

Other studies, however, suggest a relationship between increased oxytocin and reduced social anxiety. Social anxiety can be a paramount manifestation in autism, and social phobias in general translate into an apparent inability to socialize. So the question that remains is, Did the oxytocin in this study somehow directly affect social capacity in these participants, or did it lower their social anxiety sufficiently enough that they could more comfortably engage in social interpretation?

Ideas for questions

The brain releases oxytocin from the posterior pituitary. Can you identify the feedback pathway that causes this release? What other hormone or hormones does the posterior pituitary release? What about the anterior pituitary?

Oxytocin is involved in parent-child bonding. Were you aware that this “natural” bond has a hormone underlying it? Do you think that this applies only in human parent-child bonding? Research this question and explain why or why not.

One problem autistic people sometimes encounter is being too trusting because they do not recognize when someone is cheating them. Given findings in other studies that oxytocin facilitates trust in people even when they have experienced betrayal, how do you think these results might affect any effort to apply oxytocin therapeutically in autism?

Update: Belgian "coma man's" "communication" actually facilitated

Man in vegetative state not really communicating

In a follow-up to the post below about communicating in a vegetative state, a new report indicates that the Belgian man whose alleged communications first opened the window to such studies may not have been saying what was attributed to him.  Rom Houben made headlines around the world when researchers reported that in spite of his having been in a vegetative state for many years following a car accident, he appeared to be functioning at a level high enough to perceive and respond mentally to the world around him. In spite of the optimistic headlines, however, some observers expressed skepticism that Houben was doing the communicating.

Facilitated communication a bit too facilitated

As just reported in Der Spiegel, follow-up testing to address lingering questions about the report seems to indicate that Houben likely was not formulating those responses himself. Instead, the speech therapist appears to have been doing the responding. While the physician conducting the original study said that he had already tested for this possibility, further, more stringent tests demonstrated that Houben lacked even the muscle strength to have typed the responses attributed to him. It is not uncommon in facilitated communication for the person doing the facilitating to unconsciously begin communication their own thoughts or perception of the patient’s thoughts.

Not ruling out consciousness

In spite of these findings, because of the results from imaging of activity of Houben’s brain, there is little doubt that he lives in some kind of consciousness. The imaging suggests a level of activity near that of a healthy brain.  Also of interest is the fact that even though Houben didn’t pass the more stringent set of tests, another patient with a comparable diagnosis did. Thus, the quest to determine the magnitude of consciousness, perception, and response in patients diagnosed as “vegetative” continues.

Vegetative state or consciousness?

The brain is a funny thing

Brains are funny things, and neuroscientists are learning more and more every day about the unpredictability of the human brain. While a decade ago, experts might have insisted, based on their standard bedside tests, that a person in a persistent vegetative state could not understand anything being said around them, two recent reports have signaled a shift in the dogmatic wind. The first was the celebrated discovery that a Belgian man, who’d been considered PVS for 23 years after a car accident, emerged from his state and reported having been conscious the entire time. The second, just released, indicates that a small percentage of patients in a persistent vegetative state may not only be conscious but also be able to process questions and answer them accurately. In this latter study (available in full text here), investigators used a technique called functional MRI, which provides an image of the blood flow that occurs to areas of the brain that have become active.

A question of ethics?

These findings raise a number of ethical questions. Some issues of concern center on whether or not these patients might be able to express a wish to live or die, and if so, what the response should be. On a more potentially positive note, doctors suggest that they might be able to ask some presumed PVS patients if they’re experiencing pain and take steps to alleviate it if the answer is yes. Some people may remember the Terry Schiavo case, which raised a number of ethical questions about such conditions and end-of-life issues. In her case, her condition arose from oxygen deprivation. Researchers in the most recent study report that only patients who had experienced traumatic brain injury–rather than oxygen deprivation or blood deprivation–were in the group of patients who seemed able to respond to questions.

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