Do pharmaceutical companies hinder sub-typing?

As I said before, I went to a talk on Genetics Of Complex Traits. I asked a question at the end (despite my stuttering :-). She presented work where they found statistical signals on 4-5 genes for a disorder. I asked her what this finding means. Does it mean that you need all 5 genes for the disorder to develop or just one of them or a combination? She said that this cannot be found out by the statistical analysis but by trial and error in the mixing of the compound impacting the genes in a medication.

Then I asked about sub-typing. Couldn't it be that there are 5 subtypes and each one caused by 1-2 genes. She said that sub-typing is very difficult to do. Apparently, pharmaceutical companies don't like to do research on sub-typing, because they prefer to sell a general compound for everyone rather than just for a subset where they make less money!

Genetics of complex traits

Yesterday, I went to a talk on Genetics of Complex traits. I learned a lot about the least advances in genetics. The progress is driven by two fields: new technologies to extract DNA and map the genes from samples, and new statistical methods to extract more information from the gene maps. In the future, we can expect much faster gene mapping and more squeezing out information from gene maps.

So we expect more advances for stuttering. The beautiful thing about genetics of stuttering is that you dont care about stuttering at all! You just talk your stutterers and test them. No need to define what a stuttering incident is, how to measure severity, and so on. No ideological bagagge, you just analyse the sample and see what's happening.

Getting rid of a habit: finally

Some time ago, I reported on my experience to get rid of a habit: see here.

I used to be really bad in swimming crawl, because I had problems with getting the breathing mechanism right. I used to choke when water came in my mouth.

Now it is completely gone. I do not choke any more when breathing doing crawl, because I unlearned a habit.

I am wondering how much bad habit is part of stuttering? Surely, we have habits in stuttering. How can you find out how much is habit and how much is underlying difficulties? Can you say that the more you practise the less stuttering? What are the criteria to distinguish between conditions based on a bad habit or based on more underlying difficulties?

Disclaimer to reports on Pagoclone

My last post was a report of a first-person experience of taking Pagoclone. I am a bit uncomfortable that readers might consider the very positive report as solid evidence for the efficiency of Pagoclone as a medication to reduce stuttering.

There are several issues to consider:

1) A first-person experience is certainly a fact. The person truly does experience what he is reporting.

2) HOWEVER, the interpretation of what he is experiencing and why he is experiencing is an interpretation of reality. He has a theory on what is happening with him. And this is NOT, and I say it again is NOT, necessarily correct. His interpretation, his theory, could be wrong. An example: A man gives a woman flowers. She experiences positive feelings, and interprets that he likes/loves her. Her experience of being given flowers and the feelings associated are true. She also experiences her interpretation of this act, but (as many women know) her interpretation might well be completely wrong and he is just a womanizer!

3) Human often fall prey to logical fallacies, and that's why their interpretation is not be trusted in general, UNLESS the effects reported are very very strong and very many say it. But even then... But their experiences as such are mostly reliable. They truly did experience what they report.

4) Reports are "dangerous" due to the selection bias. Pagoclone might have no effect at all, and lets assume stuttering fluctuates greatly over time (as it does). Then BY CHANCE some will experience a decline in stuttering at the same time as taking Pagoclone. And they and the readers of the reports might associate this correlation with a casual link even though it is just a pure coincidence.

Experience of Pagoclone

A reader has sent me this report on his experience on Pagoclone:

The drug hasn't completely 'cured' me, but has helped tremendously. What I say to the folks in the clinic is -- am I supposed to sound like the folks on tv? So nice and so polished? Sometimes I do. Sometimes after a caffeine high, I just rip through my speech like an auctioneer.

I'm also getting a little more bold. I talk to people in public who I wouldn't have a year ago. At the pizza place, I now ask to change marinara sauce to garlic. Also, I never suffered from anxiety. I'm very laid-back. I have a rough time saying my name and introducing myself. But it's gotten a little better. I still drag out my first syllable, but it's not as long as it used to be. And I'm able to jump right into whatever I need to say so the listener doesn't think twice about it. Honestly, I feel that maybe the drug is relaxing me a bit more. That it's sort of forcing me to slow down my verbal output. It's strange. And as you said about the placebo effect, it's uncertain about what else is happening after I start speaking more fluently -- confidence builds, words are easier, I start smiling more, etc.

I've had absolutely no side effects from this as all. Then again, this is all just me. Your mileage will, of course, vary. I think once the next phase of this trial is over, I might get off the drug for a bit just to see what happens. I'm curious about the confidence effect. And the fact that I'm maybe thinking about slowing things down a lot more to make it easier. I'm also talking to my son more -- and not stuttering. He might have an effect.

Stuttering in Asia

Stuttering is relatively constant across cultures, suggesting that it is a generic problem of speech function rather than a culture-induced one.

Check out Jhong Ren's blog on Asia and stuttering.

Similar in stuttering??

I just read an article that discusses how inefficient information transfer between regions could be at the origin of autism.

Could this mechanism be at play in stuttering, too?

Transfer practise in the virtual world?

Felix wrote to me:

I have found a new study about Reality Virtual and stuttering. I believe it could be very useful for the treatment of stuttering. For the example, desensibilization, learning better the cancellations, pull-outs and onset,…etc,.etc..

The study are is, “Frequency of stuttering during challenging and supportive virtual reality job interviews”.

Link to article is here.

What is your opinion? In the future can there exist a commercial software to treatment the stuttering? Not only in interviews, but also in the bus, underground, nice girl ;-)

I have looked at the article and, to be honest, I am not convinced. It could well be useful to practise speech techniques in a safe environment. But you can do the same in group therapy with the other real participations. In any case, you still need to go out there and practise in real life situations.

And I am not sure I would be as excited by a virtual girl than by a real girl!! :-) But maybe we can have Lara Croft as the virtual girl and we need to try to chat her up! For female stutterers, I am happy for the software maker to make a digital copy of me... :-) Or alternatively, they can practise their techniques by phoning me: 00352 26835033.

Defects somewhere on the medial system?

In a previous post, I put the idea forward that thinking in terms of a defect somewhere on a circuit is a more natural way of thinking about stuttering. It naturally includes the possibility that different malfunctions are causing stuttering and that they all have roughly the same basic symptoms (because they have malfunctions on the same circuit).

The best candidate of such a circuit might be the medial premotor system (the basal ganglia and SMA). Per Alm has put this forward in his PhD thesis. I have written about it extensively, for example here. Roughly, the brain has two parallel dual premotor systems: the medial for automatic speech (where we emphasise on content of speech), and the lateral (where we emphasise on the form of speech). Of course, if we assume that the malfunction can be anywhere along the medial system (and the fibers connecting it to speech/language regions), we will not be able to get clear experimental observations as for each defect another region is affected?

The logical fallacy of NLP

Neuro-linguistic programming (NLP) is quite fashionable and controversial nowadays. It is a personal development framework based on supposedly the latest knowledge of neuroscience. It is interesting because there are many new stuff coming out of neuroscience which might help someone to change and improve their life. However, there is so much pseudo-scientific concepts floating around and so many crackpot arguments and discussions. It is a bit of a shame, because I strongly believe that understanding our brain better gives us more efficient tools to change behaviour and attitudes.

NLP is applied to many different areas. And of course, people are now using it in stuttering. Probably the most well-known advocate is Bodenhamer. There are several things that get a bit on my nerves:
1) He and others are mis-using NLP. It is fine to propose methods and frameworks to change behaviour and attitude. But they are pushing it by claiming that stuttering is cognitive rather than physiological: see website.
2) They have no proof for their theory in fact genetics and brain imaging strongly disproved their case.
3) There is no study that shows that their approach is effective.
4) They seem to believe that if you really really want you can achieve anything by re-wiring your brain. But there are clear physical limits in your ability to do so.
5) Why are they so dogmatic? It would be very easy to combine both views i.e. that is physiological and secondary effects and social handicap are strongly modulated by cognitive thought processes which can be changed with NLP or other methods.

Poll: Results

Thanks a lot for your voting!

I have to admit that I am surprised by the outcome. More than half of you would take Pagoclone even for only moderate impact. Of course, you might not be representative for the general stuttering population.

I was guessing that about 10% would take Pagoclone (or another medication), but it seems to be more.

POLL: Would you take Pagoclone?

Here is TheStutteringBrain's first poll. Pagoclone is a medication that seems to reduce stuttering according to Phase II trials. Please only take the poll if you stutter! Thx to Diego for the tip! You can leave more elaborate comments on the comments page.

Phase III of Pagoclone trials decided

This decision brings us as close as never before to a medication specifically approved to treat stuttering. Congratulations to Jerry Maguire and his team. Also, thx to Alessandro for the tip!

Indevus Announces Clinical and Regulatory Plans for Pagoclone

Company to Move Forward in Phase III Trials in Stuttering

Future Work on Premature Ejaculation Not Planned After Interim Analysis of Phase II Trial Showed Insufficient Efficacy

LEXINGTON, Mass.--Indevus Pharmaceuticals today announced that following an End of Phase II meeting with the FDA, the Company has established a clinical plan towards regulatory approval of pagoclone for the treatment of persistent developmental stuttering (PDS) and will initiate a Phase III trial in the first half of 2007. Separately, following an interim analysis of the Company’s Phase II trial of pagoclone in premature ejaculation (PE), the Company has chosen to discontinue the trial due to insufficient efficacy.

See more here.

Big $$$$$ for Indevus?

I estimate a 1bn dollar annual market for a stuttering medication.

Assume that 1% of the population stutters,
1bn people have access and can afford the medication,
10% of them would take it, and
the annual costs for the medication is around 1000$ (80$ per month).

That gives us 10 million people who could afford and have access to it, and 1 million people who would take it, and 1000 million dollars income per year.

John Paskievich and his Unspeakable

At the BSA conference, I went to the screening of Unspeakable, a documentary by John Paskievich: you can see short videos on this website. John is a well-known documentary maker who made his way to the Cannes Festival: here is a list of his documentaries at IMDB. His movie is mostly about the social impact of stuttering from his personal experience and life. I really like the documentary for its clear and uncompromising view on what it can be like to be a person who stutters. A powerful movie to share our experiences and feelings with the general public.
However, when Unspeakable deals with causes of stuttering, he is adding ketchup to a chocolate cake. He puts forward his own opinion indirectly by interviewing Darrell Dodge on the causes of stuttering who is absolutely not representative of the research community, in fact he is not even part of the research community. Moreover, Dodge's theory of "stuttering as a self-inflicted disorder of speech, communication, and awareness" is not supported by evidence, but in fact I would argue that latest genetics research contradicts it. But, I have to be fair and say that I agree with many individual statements / insights on his website, but not with his general conclusions which just show to me that he never did research himself i.e. like the pope talking about sex! By not clearly sticking to his own experience and giving his view of why people stutter John does a colossal disservice to himself, Unspeakable, and the people whose experiences he wants to get across.

Thinking in terms of circuit

Suddenly, many new ideas are popping up in my brain and floating around. Here is No 1: I noticed that I should probably think more in terms of circuits being dysfunctional rather than separate brain modules. The big advantage is that this more "system" (as opposed to local) way of thinking allows me to state that "The cause of stuttering is a defect somewhere in circuit X" rather than "For some, brain region A is not working well, in others the fibers connecting to region A and B are not well insulated". It might well be that stuttering occurs if any of the regions or fibers connecting the regions WITHIN a circuit is malfunctioning. So the goal should be to single out the circuit. So there might be a unifying way of encompassing all people who stutter, and difference can be explained by subtleties coming from where in the circuit the malfunctioning happens.

An interesting side product of this way of thinking is that there is a more natural way of asking why people with PDS seem to have inferior dual task performance. You can ask what is the region(s) that both dual-task circuit and stuttering circuit share. This would also lead to the conclusion that not all people with PDS should have inferior dual-task performances, as the stuttering circuit will NOT share all the same regions as the dual task circuit. So I would predict that only a subset of people with PDS would have inferior dual task performance i.e. only those that have a malfunctioning region / fibre, that also lies on the dual task circuit, in the stuttering circuit.

What I forgot to say at the conference

As you can see from the picture, I am moving too fast! The main theme of my brief talk was that the ability to study (and therefore to understand better) the brain has moved stuttering research in new territory. This is also the main theme of my blog. What I forgot to do is to explain why.

Ten years ago, you could formulate nearly every type of theory: a left-right conflict in the brain, the amygdala is overactive, the motor coding doesnt work well, and so on. Actually, my favourite theory is that little demon (probably female) getting drunk on occasionally tripping on the pathways that deliver the go-speak signal to the motor cortex. It is very different nowadays: If you support a theory, you need to explain all the new experimental evidence, for example:

1. Can your theory explain the genetic component?
2. If your theory focuses on a specific brain region, why doesnt it show up in brain imaging scans?
3. Why does this drug reduce stuttering?

So finally at last, you cannot just go about and say anything you like. You can still go and write about it, but you can no longer claim that you are doing research or science.

That is the real progress that is being made. It is still some way of, but theory building getting more constructive due to experimental constraints.

Zeitgeist of the BSA conference

Here are some general ideas floating around at the conference or in my brain during the conference:

1) over the last decade, more and more experimental findings are starting to constrain any theory building. Ten years ago, you could have said pretty much everything about what is happening inside the brain, but nowadays you need to face up with evidence that needs to fit your theory; a situation that many "researchers" find difficult to handle!!!!

2) there is definitely a genetic component to stuttering, but not a single gene.

3) stuttering is likely to be hetero-causal i.e. different causes lead to stuttering but on the same circuit.

4) genetic tests are going on and we should expect more research news happening. Dryana collected blood samples for his research. He run out of needles, so there was a great willingness to donate blood!

5) having a research session attached to the BSA conference worked well, and was a very cheap way of organising a mini research conference.

6) stuttering research is becoming more and more of a real science.

7) the Pagoclone study has still not published their results fully.

8) the researchers I invited seemed to have genuinely enjoyed the cross-disciplinary debate.

More soon. I have to go to Oxford to pick up my back pack that I forgot on the train. I hope it's mine!!!

Successful BSA conference.

I just came back from the BSA conference in Telford. The research section that I organised went extremely well. Everyone seemed very happy with the talks and the workshop. Dennis Dryana got many volunteers to donate blood for genetics research; he even run out of needles.

I am currently in London, and I am busy trying to get back my back pack that I lost yesterday on the train from Oxford to Reading, if you found it, let me know!! If you stole it, may god bless you with eternal stuttering! :-)

I'll update you on Wednesday evening about the conference talks. The picture of what stuttering is about is getting clearer in my view.

The new sciences of stuttering

I still have problems. But here is the first part of the description of research program at the Telford conference.

The new sciences of stammering

Over the last decade, advances in brain imaging, genetics, and pharmacology have provoked a revolution in the scientific understanding of the human brain. Scientists are now using this knowledge combined with the new research tools to tackle an age-long mystery: the mechanism and causes of stammering, and how best
to treat stammering. The BSA has invited to its annual conference in Telford leading researchers in the fields of neuroscience, genetics, and pharmacology to share with us the new sciences of stammering and answer the question: How are
neuroscience, pharmacology and genetics changing our understanding and treatment of stammering?

The main session of the program is the research plenary where leading researchers give conceptually clear and simple reviews of the progress made in their research area. After a tea break, the audience has the opportunity to ask probing questions to the panel or comment on any issues related to understanding or treating stuttering. The general sessions are followed by a research symposium where the experts will present and discuss cross-disciplinary topics.

For further information, please contact tom.weidig@physics.org
or visit the BSA website: www.stammering.org/conf.html.