Author Archive

Another Viagra Side Effect: Amnesia

September 23, 2010 20 comments

By Soman via Wikimedia

It sounds like the setup for an off-color joke, but it’s true: Viagra and the other phosphodiesterase inhibitors (definitely Cialis, and probably Levitra too) can trigger an episode of transient global amnesia (TGA), one of the more mysterious and freaky cognitive syndromes one can encounter. TGA isn’t like amnesia in the soap operas, where people awake after a coma or head injury and can’t remember their name or recognize their family. TGA is a brief episode of primarily anterograde amnesia, which is the inability to form new memories. The soap opera amnesia is retrograde amnesia, where past events are not recalled but the character can learn (or relearn) and rebuild an identity. Transient global amnesia can also involve retrograde amnesia but past events prior to the onset of amnesia are generally recalled without much difficulty. TGA resolves on its own, typically over the course of a few hours to a day, and usually doesn’t recur.

One of the most interesting things about TGA is that, although it has been well-described for decades, there is no real agreement about how it happens. There are well-described triggers: vigorous exercise, exposure to cold, strong emotional experiences, and sexual intercourse. There have been several reports of TGA after use of medication prescribed for erectile dysfunction (Viagra, etc.) but since there was also sex involved, the medication itself wasn’t considered a trigger. There have now been, however, two cases published where someone had TGA after taking an ED medication and NOT having sex.

Generally, theories about TGA fall into two categories: seizure and vascular events. Given the nature of the known triggers, and the known vasodilatory effects of ED medications, these reports would seem to favor a vascular explanation. We do know that Viagra and its kin have vascular effects that encourage erections (after all, that’s the point) but they often cause headache as well, implying that they are also vasoactive in the head.

Bob Dole, Viagra pitchman

TGA is a fascinating syndrome to observe and diagnose. Sufferers typically are somewhat anxious and aware that they are experiencing something unusual. Characteristically they will ask the same questions repeatedly: usually asking why they are in the hospital, how they got there, or what they did that day. They rarely become agitated, which is somewhat surprising until you realize that to become agitated one must hold onto the idea that something is wrong or upsetting. Patients with TGA are easily reassured, for a few seconds or minutes at a time. Gradually, they can hold information for longer and longer periods until their memory is essentially restored. They do not regain memory for events that happened during the episode. It is most likely that whatever vascular changes lead to TGA involve the hippocampus, both because this is where short-term memories are encoded and also because there is some MRI evidence that some TGA patients have slight tissue loss in one or both hippocampi. The best thing about TGA, compared to most things a neurologist or psychiatrist will see in the Emergency Department, is that the prognosis is excellent. Most patients are entirely  back to themselves within a day, and most will not have a repeat episode. In the past it was believed that the recovery was uniformly complete, but some studies that follow TGA patients indicate some residual but subtle cognitive impairments. TGA is fairly rare: Dr. Wikipedia gives the annual incidence in the USA as about 3 per 100,000, but that increases to 23 per 100,000 among those over 50.

You might think that this is a major side effect that would discourage use of these medications, but I have a feeling that if men can ignore concerns about vision loss, cardiac events, and prolonged painful erections, then worries about transient global amnesia won’t begin to make a dent in their blockbuster sales.


Schizophrenics Can Tickle Themselves

September 21, 2010 11 comments

By David Shankbone via Wikimedia

No, it’s not because they have “split personalities.”

In a previous post on contagious yawns I mentioned self-tickle as another interesting and fun pop-neuropsychiatric topic. At some point most of us have probably wondered what the heck is up with tickling? (not to mention $%#*#@ magnets, how do they work?) The question of why we can’t tickle ourselves came up a few weeks ago in a conversation at work, and while my colleagues smiled and shrugged and moved on, I thought “somebody must have studied this, they’ve studied pretty much everything else I can think of.” Indeed, a quick PubMed search led me to a paper simply entitled “Why Can’t You Tickle Yourself?“.

Asking “why” is of course tricky, and one could easily come up with evolutionary explanations of how distinguishing self-touch from external touch would be beneficial in a world where we slept on the floor of caves with poisonous creepy-crawlies all around. This paper actually looks more at “how” the phenomenon of self-non ticklishness comes to be.

The basic idea is that as the primary motor cortex is signaling down the corticospinal tract to get our muscles to move, these signals are interrupted and modulated by the cerebellum, which provides a kind of buffering. When working properly, the cerebellum allows movements to be smooth, an appropriate speed, and to start and stop in the right places. It appears that the cerebellum also sends a signal to secondary sensory cortex and the anterior cingulate gyrus that indicates what movement is planned. In English it would be something like “ok, we’re swinging the leg forward to walk now, please ignore the sensation of pants rubbing against the knee.” This gating of sensation is well-described: it’s how we tune out frequent unimportant stimuli, and you can easily see why it’s an important ability to have.

It turns out that if the cerebellum alerts these areas to a movement that will contact another body part, the input from the appropriate body part is gated as well. This makes the sensations of self-tickling just predictable enough so that they aren’t, well, ticklish. The investigators used a sort of tickle-robot that the subjects could use to tickle themselves. When the robot moved in concert with the controls moved by the subject, it wasn’t very ticklish. But if the robot’s response were delayed a few hundred milliseconds, or if the direction of movement was skewed, it became more ticklish. The less the robot movements correlated with the actual movements of the subjects at the controls, the more ticklish the stimulus.

So now we know that we can be tickled by robots and that we can’t tickle ourselves because we can’t surprise ourselves. The study goes further, however. The authors suspected that psychotic symptoms such as auditory hallucinations or the feeling of being controlled by an external agent were related to a disruption in this feedback system. Both of these symptoms are often characterized as the inability to recognize one’s thoughts and actions as one’s own, leading to the logical belief that they originate externally.

So what happened when psychotic subjects tried to tickle themselves? (For some reason, the psychotic subjects didn’t get to use the robot. Perhaps because the investigators didn’t want to write in the grant proposal “we’d like to build a tickling robot and watch psychotic people tickle themselves with it.”) The subjects with psychotic symptoms found that when they tickled their own hands, it was no less ticklish than when the experimenters did it. This is a little ambiguous: it means that either schizophrenics aren’t ticklish or that they can tickle themselves. I choose to believe the latter.

It’s medical dogma that some dread illnesses have persisted because they confer some advantage to those who carry them: sickle-cell trait protects against malaria, cystic fibrosis protects against typhoid fever. Being able to tickle oneself is small comfort for having schizophrenia, but at least it’s something.

Blaming Amen: Nuclear Psychiatry or Unclear Medicine?

September 20, 2010 34 comments

The latest American Journal of Psychiatry arrived in the mail last week, and when I got around to the letters section, I found a letter from Daniel Amen objecting to a critique of his work following a review of his book from last year. Apparently his book, Healing the Hardware of Your Soul, was criticized pretty harshly in the original review, published in AJP in March 09. Amen’s liberal use of nuclear brain imaging, primarily SPECT scans, to diagnose and guide treatment of psychiatric conditions took some pretty heavy fire.

The original review of his book, which I missed last year when it came out, was pretty clear in its criticism of his claims:

For each of the vignettes Dr. Amen presents, many psychiatrists would have chosen treatments similar to those he used when confronted with the particular symptoms he describes, based solely upon clinical judgment. There is no systematic analysis of the 45,000 imaging studies to demonstrate how Dr. Amen’ s approach is superior to treatment-as-usual by a psychiatrist. Thus, there is also no evidence presented to justify exposing patients to the radiation of a SPECT scan and to support the considerable expense to patients, families, and their insurers.

Things were apparently quiet, and the review attracted little attention until May of this year, when two writers in the letters section decided to pile on. They entitled the letter “Scientifically Unfounded Claims in Diagnosing and Treating Patients” and began by reiterating the claims of others that Amen has scanned thousands of patients unnecessarily. They went on to accuse him of endangering the profession of psychiatry, because his work could discredit the use of psychiatric functional imaging and prove to be a setback to others who are presumably doing more “legitimate” work. They end the letter with a sort of threat:

It is therefore incumbent upon all of us to monitor and regulate our field. We encourage physicians to remain vigilant of unproven approaches practiced by our peers and to immediately report these trespasses to their state medical boards.

I guess Amen felt he had to respond to this one, because in the current AJP he writes in, defending his work and attempting to cite other evidence that supports his use of imaging. His arguments are selective, however, and I don’t think he quite succeeds in proving his point. The editors of AJP apparently don’t either. After his letter, they printed the response of the original letter-writers who pretty much take apart each of Amen’s points. And then there’s a note by the editor-in-chief of AJP, which ends with:

Commercialization of a diagnostic test, even if the underlying procedure such as brain imaging or DNA analysis is approved for human use, strongly indicates to physicians and families that the test adds significant new information to guide clinical judgment. We have published this exchange of letters as part of our responsibility to readers to point out when a procedure may lack sufficient evidence to justify its widespread clinical use.

In case you’re not familiar with Dr. Amen, his books, or the Amen clinic, you can think of him as the Neuropsychiatry equivalent of Dr. Oz. Whenever Oz or someone like Andrew Weil or Dr. Drew comes up in a conversation among doctors, there is often a collective sigh or rolling of eyes. Yes, these are real physicians, but they are thought to have lost their academic edge, or even a bit of their medical integrity, by pushing the envelop of evidence-based medicine to endorse dubious treatments, sell their own products, or sensationalize otherwise legitimate treatments. Mostly the supplements, alternative medicine modalities, and exercise regimens they tout are at worst harmless and in many cases may in fact be beneficial. The harm they do is more implicit: their statements as doctors imply that their endorsement of the benefits of astragalus root, say, have the same weight of evidence behind them as the aspirin for secondary prevention of heart attack that the TV viewer’s own doctor is likely recommending.

In Amen’s case, it’s his contention that SPECT scans are an important addition to the routine diagnosis and treatment of mental illness. For several thousand dollars, you can visit his clinic, have a SPECT scan, and then have a treatment plan recommended which is supposedly informed by your SPECT. The objection that most psychiatrists have is that Amen’s recommendations are not much different than what a psychiatrist would do without having a SPECT to look at. The SPECT scans give his practice a veneer of scientific legitimacy that is misleading. Not many people would pay $3375 out of pocket and travel out of state for a psychiatric consultation, even if the psychiatrist is said to be quite good. But a psychiatrist who uses high-tech imaging your local doctors won’t offer, who can “look into” your brain and make recommendations based on a striking color image instead of by just talking to you? This gets some people excited, and I’m sure that Amen has better than average treatment response, at least in the short term, because he has motivated patients and offers them a strong placebo.

Overall, I think people like Oz and Weil are earnest and encourage people to be engaged in their own healthcare, which is certainly good. I think that their work, however, would be more respectable if they held their TV statements to the same level of credibility that we hold statements in peer-reviewed journals. This is a tall order, because in science, accuracy means ambiguity, and ambiguity doesn’t make good television compared to the Shocking New Finding that isn’t really as significant as it sounds. We know that it’s possible to be a good physician-commentator: I think Sanjay Gupta does pretty well, and Rich Besser at ABC and Darshak Sanghavi are top-notch. I don’t have a very good feeling about Amen, however. He’s not in the business of spreading valid information and making sound recommendations to help people interpret health care news or their own illness. It’s more like he’s making dubious self-serving claims at the expense of a vulnerable group of people: those with mental illness who feel they haven’t had adequate treatment. I think that’s what bothers me the most.

So where does Dr. Amen sit in the spectrum between conservative academic and self-serving sensationalist? Clearly I think he’s closer to the latter, and the reviewers at AJP appear to agree. I firmly believe that we will someday be able to use neuroimaging, both functional and structural, to diagnose and guide treatment of psychiatric disorders. That’s in part why I became a neuropsychiatrist. I don’t know, however, when that will come to be, or even if it will be during my career or lifetime. On the other hand, Dr. Amen knows, or claims to know, that that time is now. He uses functional neuroimaging to help diagnose and treat mental illness, and appears to make a good living at it. I truly hope that what he’s selling will indeed be available some day, but nobody, Amen included, has provided adequate evidence that nuclear imaging can do what he says it does. There are certainly valid uses for SPECT scans today, for example in assessing damage after a traumatic brain injury or clarifying a diagnosis of dementia. For the vast majority of psychiatric illness, however, having a SPECT scan at the Amen clinic or anywhere else will only add a small dose of radiation to your lifetime exposure and large hit to your wallet.

The Introspection Nucleus

September 17, 2010 4 comments

By Todd Martin via Flickr

A study in today’s issue of Science concludes that the size of a small area of the right prefrontal cortex correlates with “introspective ability.” I wonder if, in the coming years when meta-irony is bound to be king, whether “prefrontal cortex-gazing” will replace “navel-gazing” as an epithet for introspection.

There are certainly limitations to the study, but there is also a kind of charming quixotic quality to it. The researchers very cleverly designed a task to measure subjects’ introspective abilities. Basically, they were given a challenging visual task and then asked to estimate their accuracy on the task. The more closely their self-perceived accuracy matched their actual accuracy, the higher their meta-cognitive or introspective ability was rated. This is certainly a type of meta-cognition, but I don’t think it’s what most people would think of as introspection. It’s more narrow. I also wonder whether they were really measuring simple estimating ability: it would have been illuminating to ask participants to make other estimations as well. Perhaps this area of cortex is also responsible for weight-guessing or estimating how many gumballs are in a jar.

That being said, it’s tempting to think of this discrete prefrontal region being a kind of self-judge, like a little demon watching the rest of the brain chug along and clicking his tongue at all the foolishness. If there is a single area associated with introspection, it would make sense for it to be in the prefrontal cortex. Anybody who’s worked with patients with frontal lobe injury knows that “self-aware” is about the last term that would come to mind to describe them. I have a hard time imagining how this study will benefit my head injury patients, although I know that somewhere down the road, this will have contributed to a useful treatment. It’s hard, though, to share in the excitement of the researchers. This is typical of the differing perspectives often seen in research/basic science compared to clinical practice. Researchers often are so focused on obtaining a bit of information that it becomes the entire goal. Successfully obtaining the data, no matter how arcane, is the victory: “OK, we found it. Now we know. Done.” The clinician, however, is sitting in a small exam room with someone who is suffering, and often just wants something that will help this poor soul, whether anybody understands how it works or not. We are taught to avoid academic data-gathering in order to avoid over-testing, exposing patients to risk, and driving up health care costs. The mantra becomes “If it’s not going to change what I do, then I don’t even want to know.” These are two different cultures with different values, customs, and languages. This is why bringing research to the clinic is known as “translation.”

Aside from the issues of practicality and methodological nit-picking, I have a hard time taking studies like this at face value. It is hard to imagine that something as complex and elusive as “introspective ability” could be caught and bottled so easily. Not only is it daunting from a neuroscience point of view, but it’s also kind of anti-poetic. But at the same time, I do believe that introspection, along with the rest of consciousness, is a brain function. Holding that belief requires accepting that these things are all describable and reducible to individually meaningless neuronal firing. So although it pains me in a vague and slightly embarrassing way, I am happy and grateful that somebody is doing these studies.

So That’s How Antidepressants Work (in mice)!

September 16, 2010 3 comments

By Rama via Wikimedia Commons

In the September 17 of Science, a new mouse study of SSRI effects finds that there is a microRNA that is upregulated by SSRIs, and which affects expression of serotonin transporters. This is presumably in addition to the direct inhibition of the reuptake pumps by the drug itself. It’s an interesting new piece of info that helps explain how these drugs work, which is surprisingly mysterious given how widely they are used.

Most people, even many psychiatrists, will tell you that they work by increasing the amount of serotonin in the brain (or if they’re really trying to be smart, the amount of serotonin in the synapse). It’s true that these drugs do in fact do this (in the synapse): it makes basic sense that if you stop reuptake, there will be more serotonin left in the synapse. But does this treat depression and anxiety? Are these maladies simply caused by a lack of serotonin in synapses, or perhaps an insensitivity of the post-synaptic cell which then requires extra serotonin to be activated? These common explanations, again, even by some psychiatrists. But they are wrong. If all we needed was more serotonin in the synapses, then these drugs would work immediately. SSRIs would work just as fast as Tensilon and amphetamine, which increase acetylcholine and dopamine in synapses respectively. It’s well-known that SSRIs take 4-6 weeks or more to take effect, and it’s even more well-known that amphetamine works immediately. So it should be obvious that SSRIs have effects that depend on something besides dumping serotonin into our synapses.

I’m not going to tell you exactly how SSRIs work, because I don’t know. And I don’t know anyone who does. It is likely that by increasing the amount of serotonin in the synapse they affect the sensitivity and/or expression of presynaptic receptors (autoreceptors), thereby effecting subtle changes in the sensitivity and overall reactivity of the serotonin networks. This kind of response would in fact be expected to take a few weeks.

But then there’s norepinephrine.

Image courtesy of Odile Kellermann via AAAS

To me, the interesting thing about the current study, even if it’s just in mice, is that the researchers have demonstrated that SSRIs appear to have downstream effects that include promoting expression of serotonin reuptake in noradrenergic neurons. This is mapped out in the cartoon here. I’m not a molecular biologist, so I can’t and won’t get too deep here, but in this mouse model fluoxetine (Prozac) sensitizes noradrenergic neurons this way, and also inhibits GSK3β. Before today I had never heard of GSK3β, and I don’t know if this is truly meaningful, but Dr. Wikipedia says that another drug that inhibits GSK3β is lithium! Another effective drug that we really don’t know what it’s doing. GSK3β appears to have a number of activities, and one that is interesting is phosphorylation of Tau, the protein that is found in the “tangles” of Alzheimer’s.

I once asked an experienced psychiatrist why he prescribed so much Cymbalta. (Cymbalta is an SNRI, so it works directly on both serotonin and norepinephrine.) His answer was that, although he continues to use SSRIs extensively, he feels that the responses from patients are not as robust as he used to see in the days when he prescribed mostly tricyclics. He thought this might have been from the noradrenergic effect of TCAs that was presumably missing from SSRIs. Now that he has Cymbalta available, he often uses it as a first choice and feels the response is better than from SSRIs.

So maybe the effect from SSRIs is really due to this other effect, however weak, on the noradrenergic system. This would be a blow to the Serotonin Hypothesis purists, but not to the utility of the medications and the patients who benefit from them. It’s unlikely, however, that SSRIs work in only this way. There remains abundant evidence that serotonin itself is somehow implicated in mood and anxiety, so norepinephrine can’t be the whole story. Perhaps, however, it’s been serotonin’s silent partner all along. And maybe these mice brains and their microRNA-16s will help norepinephrine get the co-star billing it deserves.

Thimerosal: It doesn’t cause autism, and it’s not even in our vaccines, which also don’t cause autism

September 16, 2010 7 comments

by Pete Souza via The White House

Yet another addition to the burgeoning mountain evidence of vaccine safety: early exposure to thimerosal doesn’t cause autism. You may remember that thimerosal was targeted by the anti-vaccination autism advocates as a dangerous mercury-containing agent that caused brain damage in children who were victims of vaccination. At face value, it seems natural to be concerned about exposing our children to mercury. The autism concern with thimerosal, however, was misplaced from the beginning, as it ignored at least one key fact: the vaccine most railed against by autism/vaccine crusaders, MMR (measles, mumps, rubella), NEVER contained thimerosal. Secondly, due to (this misplaced) concern regarding its safety, vaccine manufacturers began removing thimerosal from their products in 1999. Lo and behold, autism rates have continued to climb. You don’t have to be a scientist to follow the logic here.

Of course, we are only discussing this because there is still significant public campaigning against vaccines. This despite the nearly two dozen studies, many large and well-designed, that have consistently shown the absence of a link between vaccination and autism. Compare this with the only high-profile study to claim to demonstrate a link, which was retracted by the journal and renounced by all but one of its authors, who appears to be the least credible of the group.

Why was thimerosal removed from the vaccines, then? In developed countries it is not necessary as a preservative. It continues to be an important ingredient in vaccines used in developing nations where extended and poorly-controlled storage of vaccines is more common. And the American Academy of Pediatrics felt there was little to no downside to requesting its removal. This was true from a medical point of view. From a political perspective, however, this was apparently a mistake: the call for removal of thimerosal by a mainstream medical body gave fuel and a flash of credibility to the growing anti-vaccination movement. Since then, many resources, including high-profile celebrity advocacy, that could have been helpful in making real progress toward understanding, treating, and preventing autism have been diverted.

This all wouldn’t be so bad if it were just typical scientific wheel-spinning while research found its appropriate direction. There is real damage being done, however, to the credibility of vaccination as a whole. I believe that vaccination is the single most important innovation in medical practice ever (even more important than the beloved draw-a-clock test!). One of the secrets of medicine, which is rarely brought to attention, is that we cure almost nothing: infections, some cancers, and some problems amenable to surgery. Heart disease? COPD? Dementia? Hypertension? Schizophrenia? In most cases, the best we can do is to manage it. People can do very well, but at the cost of indefinite treatment. How can we decrease the overall disease burden the best? Keep people from getting sick in the first place. And the best way to do that is: diet and exercise. OK, so we need a more practical recommendation. The answer is vaccination!

Vaccines prevent deadly and debilitating disease. Vaccines do not cause autism. Are there risks to getting vaccinated? Yes, but they are much lower than the risks of NOT getting vaccinated. EVEN IF vaccines are the sole cause of autism, WHICH THEY AREN’T, it would still be worth getting vaccinated. Don’t believe me? Ask Penn & Teller.

Why aren’t yawns contagious in autism?

September 15, 2010 45 comments

By Jesslee Cuizon via Flickr

A nice little study in the Sep/Oct issue of Child Development found that children with an autism diagnosis are less susceptible to contagious yawning than “neurotypical” children. My first reaction was happiness that someone is studying this. Contagious yawning is one of those pop-neuropsychiatric phenomena that I am likely to be asked about at a cocktail party, and until now I had nothing interesting to say about it. Another example is the age-old question of why we can’t tickle ourselves, which itself will be the topic of a future post in these pages. Most people’s first reaction to the contagious yawn/ASD study is likely to be “so what?”

If you think this study is an example of frivolous research, you may be even more upset to know that this is not the first study to address this issue. In the previous work, children were observed while watching a video in which people occasionally yawned: again, autistic kids yawned less than the controls. The new study used live interactions, and also included an observational study of typical development that found that contagious yawning begins around age 4.

So why on earth do we care about this? The hypothesis of the investigators, and I think they’re right, is that contagious yawning is a manifestation of the very basic mechanisms of empathy and socialization, which we know are impaired in autism. It’s well-known that in conversations we tend to mirror our conversation partner to a degree that usually correlates to our attachment to and interest in them. Many self-help books on sales and persuasion encourage deliberately mirroring people to exploit this mechanism and increase the trust and comfort level of your acquaintance (or target, as the case may be). Yawning is also a lot easier to observe and quantify than empathy. Even better, contagious yawning is something that can be tested in an fMRI or with other functional imaging. If we believe that children with autism have a deficit in this basic function, and we can find out how and where this function develops in the brain, then we just might learn something interesting about the neurobiology and development of autism. In fact, the authors go so far as to suggest certain brain areas are involved, the insula and anterior cingulate cortex to be precise. This isn’t the first time these areas have been implicated in autism. In fact, they seem to be implicated in just about everything. But it’s nice to accumulate any concrete evidence we can get.

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