Friday, June 29, 2007

Discussion round at ISA2007

From left to right: myself not looking at the camera, Paul Brocklehurst, Suzana Jelcic (conference organisor), Thomas Kehoe (CasaFuturaTech), and Alan Falck (VoiceAmp, thx for the picture)

Thomas and Alan are selling AAF devices. I tried out them out their AAF device. It forces me to slow down, and this makes me more fluent. I am a bit irritated by the noise in my ear(s). Maybe I should try it out longer.

Thomas Kehoe said that in stuttering there is no placebo based on the result from one study, but I replied that I don't buy it. I rather defend the general principle that there is always a placebo effect, and that the study must be wrong/misleading than give up the general principle. But I also said that the more studies are out, the less I will defend the general principle. But I am pretty confident that there is a placebo effect: we saw it in the Pagaclone study. I will write a more detailed post on the devices.

Subtypes in stuttering

Here are some possible factors that might help divide people who stutter into different sub-types. Here, sub-type is on the cause of stuttering, not on any symptoms like covert vs overt, speech with many blocks vs speech with many fillers/hesitations, etc.

-people who have stuttering genes/gene combinations that cause stuttering vs people that dont.
-people who have stuttering genes/gene combinations that increase probability of having a stutter vs people that dont
-people who have stuttering genes/gene combinations vs people who had a neurological incident
-people who started stuttering at age 3-5 vs people who started stuttering later.
-people who improve/worsen fluency with drug A vs people who are not impacted.
-people who have long-term gains in fluency after therapy vs people who dont.
-people who started stuttering and recovered vs people who never recovered.

Factors that are no relevant in my view to divide into groups with different causes:

Wednesday, June 27, 2007

Interesting symposium in August

Per Alm has organised a symposium on stuttering in Goteborg: look at Monday morning August 20th in the conference program. Here are the speakers and the title of their talks:

Per Alm, Ph.D. neuropsychology, Lund University, Sweden: Can stuttering be understood from a neuropsychological perspective? A brief overview of research and theories, with special focus on the basal ganglia and the "dual premotor model".

Hans-Georg Bosshardt, Professor, Group for Language and Cognition, Ruhr University Bochum, Germany: Incrementality and modularity in speech production and stuttering: behavioral and electrophysiological data, and discussion of the neurophysiological basis of these processes.

Gerald Maguire, Professor, M.D., Dept. of Psychiatry, University of California, Irvine, USA: Neurochemical and pharmacological experiences from stuttering.

Lutz Jäncke, Professor, Dept. of Neuropsychology, University of Zurich, Switzerland: Neuropsychological research on stuttering.

Katrin Neumann, Ph.D., M.D., Frankfurt University, Germany: Brain imaging of pathology and mechanisms of recovery in stuttering.

Tuesday, June 26, 2007

Qualifications you need

Here are the qualifications you need to be the first to understand PDS completely. You need to have an good understanding of or need to be:

1) neuroscience.
2) brain scanning techniques.
3) brain pharmacology.
4) statistical methods.
5) genetics.
6) stuttering treatments from patient and therapist perspective.
7) psychology
8) what it feels to be stuttering yourself (ideally, covert, moderate, severe, and recovering)
9) how to network with other researchers
10) getting funds for your research.
11) how to be a very good scientist.
12) high intelligence.
13) good organisational skills.
14) a good orator for conference talks
15) a walking wikepedia and literature review.
16) creative to have good new ideas
17) expertise in audiology.
18) computer programmer.
19) expertise in mathematical modelling

Any more?

Monday, June 25, 2007

Sub-types or not?

Every so often I have a "moment of inspiration". Here is my last one! :-) It's on sub-types in stuttering, and how the power of brain experiments could be improved using knowledge from empirical pharmacology.

1) It is not clear whether there are sub-types or not. However, if sub-types exist, they will significantly complicate any experiment. I mentioned the issue of false negative in my last post, where a compound might not be effective enough in a random control trial because only a minority significantly benefits and the majority not at all. There could be two sub-types, A and B, and the compound is only effective for type A. Or, let's imagine brain scans. And let's assume stuttering is caused by an underactivation of region A or by an underactivation of region B. Of course, in brain research, controls are compared to a mixture of type A and B stutterers. The signal analysis would show an underactivation in both A and B but with only half the strength, and a statistical test might show not statistically significant signals. To conclude, sub-types significantly dampen signals. The same phenomenon could occur in stuttering therapy evaluations.

2) There is somewhat evidence for sub-types. People who stutter seem to react differently to different medication, or drugs like alcohol, dope, or ecstacy. Also, some people seem to react much better to speech therapy that others.

3) There are also theoretical considerations. Speech is a very complicated multi-step and parallel process. However, the effect that characterises stuttering is simple, the absence of an appropriate signal. So many different malfunctions in this complicated process could go wrong, which would lead to the same symptom, the absence of the appropriate signal. Imagine a news speaker reading from a prompter. She will stutter if the prompter gets stuck. But this getting stuck could have several different causes: computer crash or slow-down, the editor did a mistake, and so on. Viewed from this perspective, it would be very surprising if there were no sub-types!

4) There is a chicken and egg problem, because we cannot know whether sub-types exist and identify them because our experiments do not have enough power because we do not separate the sample into different sub-groups!

Here is my solution:
a) put people who stutter in different group according to their reaction to medication or drugs.
b) do brain scans by comparing a sub-group to controls.

This will allow to get much better signals. So again, use empirical pharmacology to form sub-groups and analyse them.

Tuesday, June 19, 2007

False negatives might be a big problem

I have just changed my view on trials after another email by Willme:
With [Correction Tom: Assuming] several possible (neurotransmitter) causes of stuttering identified, the test results for any one drug applied to a seemingly homogeneous group of stutterers will be diluted. The majority may not respond at all. Morever, even if heterogenity is recognized and a subgroup of stutterers is identified (say responding to BZ's) any one particular BZ, like ativan, may not work for all of them. So the test results could be even further diluted. What this means is that the likelihood of "false negative" test results may be more of a threat than "false positives." With false positives, you take the drug and if it is not efficacious you stop taking it. False negatives imply that a promising drug for a subpopulation of stutterers may fall by the wayside forever.
I hope that there are active research programs out there involving DNA studies to identify the cause(s) of stuttering. I'm quite convinced that genetic markers will need to be found for any substantial further progress.

He is completely right in that a medication that works for a small subgroup will be rejected in a standard random control trial. And everyone thinks it's not working. Different stutterers also react differently to real drugs. Per Alm wrote about this in his PhD thesis. So we need to be able to discriminate between different subgroups, and that's very very difficult because it means we understand stuttering!!! Our best hope is genetics, but we also know that not all stuttering is genetics. So this is not an easy avenue either.

I could even turn the argument around, and say that because no trial has been very successful so far, stuttering must have subtypes.

And then I could argue that drugs that do work, must be acting on secondary symptons and not on primary causes. And this might be the case with Pagaclone.

Check out this NY times story on "On the Horizon, Personalized Depression Drugs." for inspiration on what could happen for stuttering.

Guest-Blogger Willme on ativan (I)

Willme is my next guest blogger and talks about his experiences with legal drug prescriptions and their impact on his stuttering. Interesting thoughts, and he has a PhD in physics like me. :-)

I started stuttering in early childhood. My first experience with speech therapy occurred when I was 13 years old. The therapy involved voluntary repetitions of the first syllable of each word uttered and the application of this technique in a public context. This approach didn’t work for me. I basically refused to practice this technique in public—perhaps I was too embarrassed, self conscious, etc.
When I started puberty very late at the age of around 17 my fluency substantially improved. I joined the National Forensics Society and on the debate team and engaged in forensic speaking. By the time I entered the 12th grade, my disfluency had returned. Maybe temporary changes in brain chemistry at the start of puberty offered a temporary “cure?
My next speech therapy occurred in my later 20’s after I completed graduate school. It was a group therapy setting with four other males in their late teens and early 20’s. There did not seem to be any particular therapy techniques involved other than making eye contact and the admonition to “just stop it.” Well, strange as it seems, it worked for me. Within two weeks, I became, as far as I could tell, perfectly fluent within that group context. So I called it the “power of positive thinking” (POPT) or the “mind over matter” (MOM) approach. For the next couple of months before I left the group, the POPT/MOM approach did not work for the four other people.
I then started four years of psychotherapy (twice a week) and began teaching in a graduate program at a university. The POPT/MOM approach tided me over but I found that for anxiety inducing situations (speaking before a class or at a conference) I had to expend a huge amount of energy preparing myself, both content-wise and emotionally (psyching myself up?). Also, during psychotherapy, I found that I would be disfluent when discussing emotion laden subjects.
After years of teaching and research, I moved to a career in consulting. Public presentations were fewer than in the teaching career but the POPT/MOM approach still worked (still requiring a huge expenditure of energy). A few years into this period I began to take ativan (Lorazepam) for anxiety and eventually found that at a 2 mg dosage virtually eliminated disfluency. And there was no need for extensive content/mental preparation before presentations. I would merely engage in “normal” preparation, take 2 mg of ativan about a half hour before the presentation (on an empty stomach) and, miraculously, I was perfectly normal.
My last eight years I returned to a career in university teaching and continued with the ativan therapy. I would teach two graduate courses per term and present papers at approximately 4-5 conferences per year. The courses might be scheduled say for Monday and Thursday between 6pm-9pm and the 2 mg of ativan tided me over for the three hours. So my intake of ativan was sporadic rather than regular, which is important because ativan can be addictive, its effect lessens if used regularly, and, hence, you may require larger dosages. I would certainly not recommend the use of ativan to anyone who is an addictive personality. be continued...


Monday, June 18, 2007

Guest-Blogger Willme on why ativan might work for him (II)

Let’s try to understand what’s happening from the research perspective. Given that ativan 2mg has worked so well for me, I am puzzled that no one else among the estimated 3,000,000 stutterers in this country has discovered its efficacy. Am I the only one for whom this drug therapy works? If it works for other stutterers, for what fraction of them is ativan effective? Is what I’m experiencing a placebo effect whereby I go from some level of disfluency to virtually a zero score on the stuttering severity instrument?
Ativan (technically known as lorazepam) is a benzodiazepine (BZ), which binds to the BZ receptors in the brain. BZ receptors seem to be coupled to receptors for the inhibitory neurotransmitter gamma amino butyric acid (GABA), which is the most prevalent neurotransmitter in the brain. BZ and GABA receptors coexist together in an interactive complex known as GABA-BZ (Receptors, Restak, R.M., Bantam Books, 1994, pp 166-167). BZ’s (the most notorious of which is valium), inhibit anxiety just like GABA. So ativan is regarded as a GABA agonist since it binds to GABA-BZ receptors and when it does neurons are less likely to discharge. Correlates of anxiety involve excitation (more rapid firing of neurons) and BZ’s reduce this excitation. By the way, previous studies have shown the ineffectiveness of BZ’s with respect to improving fluency (The pharmacology of stuttering: a critical review, Am Journal Psychiatry. 1991 Oct; 148(10):1309-16.Brady JP). One of the studies cited in this review that I acquired used valium (diazepam) at 5 mg dosages. I don’t know what the conversion over to ativan dosages is.
Now most of you have heard of pagaclone, currently in phase III trials as a palliative for stuttering. Pagaclone is identified as a partial GABA agonist, the “partial” referring to its lack of sedative and withdrawal effects. It too binds to the BZ receptors. The most recent press release of Indevus Pharmaceuticals indicates that phase II trials have been a roaring success in reducing disfluency. The way that pagaclone was identified as a potential palliative for stuttering was that in previous trials testing it as an anti-anxiety agent there happened to be at least one stutterer in the test group and he (she, they) reported a marked improvement in fluency levels. So to answer one of my questions above, there are at least two of us who recognize that GABA agonists/partial agonists may greatly improve fluency. To my knowledge, pagaclone was never released as a prescription drug to treat anxiety (in spite of claimed success in the anti-anxiety trials), so the possibility does not exist for our buying it and using it off label for disfluency.
A second major research direction in the current pharmacological treatment of stuttering. involves basal ganglia/dopamine system (BG/DS) theories. This line of research seems to be mutually exclusive from the GABA/pagaclone efforts or, at least, researchers have not yet found any connection between them. The BG/DS theories revolve around malfunctions in the basal ganglia very deep in the brain and the presumed production of too much dopamine, which is another neurotransmitter. Dopamine is associated with addictive illegal drugs, Parkinson’s disease (a lack of dopamine), and reward systems. Risperidone is a dopamine antagonist and has been claimed to improve stuttering in clinical trials (for a good review,see Stuttering and the Basal Ganglia Circuits: A Critical Review of Possible Relations, Alm, P. in Journal of Communication Disorders 37, 2004, pp 325-369). This review article also cites studies in which stimulants were used to increase dopamine resulting in improved fluency. So the author of this article concludes that there may be two types of stutterers, ones who improve on dopamine antagonists and others who become more fluent on dopamine stimulants.
Incidentally, I’ve tried the antianxiety drug Buspar which binds to dopamine receptors ( a moderate affinity for D2-dopamine receptors) and reduces the influence of dopamine (a dopamine antagonist?). I found it has no effect on either my fluency or my anxiety. Fifteen minutes after ingesting the drug I get a buzz in the brain and feel spacey for about half an hour. And even more incidentally, I’ve tried a variety of antidepressants (serotonin uptake inhibitors only) and these have had no effect on me whatsoever.
So the question is: Are there indeed different subclasses of stutterers who respond to different treatments—those with not enough GABA, those with too much dopamine, those with not enough dopamine, etc. Having trained as a scientist, I would prefer to follow the “law of parsimony,” and try to explain a phenomenon with a single theory rather than a collection of theories. But nature may not be so neat. If the subclasses of stutterers multiply, then it may be very difficult to get positive results from clinical trials. For example, if only some fraction, F, of stutterers respond to pagaclone, and that fraction F is too small (say less than 10%), then the trials may not be able to identify significant differences between the group receiving the drug and the one receiving a placebo. In addition, if the fraction is too small, the drug company may feel it not worthwhile to market the drug.
To answer the question as to whether the fantastic results that I experience with ativan 2mg is a placebo effect, I have some anecdotal evidence to offer. Several times before teaching my 3 hour graduate class I had forgotten to take the ativan and found at the start of class that I was disfluent. After several minutes of this I realized what the problem was. The second bit of evidence occurred at a conference in Texas at which I was giving a presentation. The presentation was scheduled just after lunch and prior to the presentation I had a Tex-Mex meal which impeded the ingestion of the ativan that I did take after the meal but before the presentation. Once again—a lack of fluency. While this evidence isn’t as good as a controlled double blind experiment, at least I’m convinced that we don’t have a placebo effect in play here.
Given my experience, you can understand my enthusiasm for the pagaclone trials. Like most of you I’m impatient to try it, but I think it will be more than a year before it comes on market, if indeed it reaches market. Then we’ll have to worry about price gouging by the pharmaceutical industry.


Saturday, June 16, 2007

Pagaclone open-label release misleading??

Here is what Indevus wrote about the new open-label results for Pagaclone:

The open label data demonstrated an improvement in nearly all efficacy measures compared to baseline that was at least double the magnitude seen in the initial 8 weeks of double-blind treatment. During the 8-week, double-blind portion of the study, patients who were randomized to placebo experienced a mean reduction in the percentage of syllables stuttered of 5%. After three months in the open label portion of the study, these same patients experienced a 31% mean reduction. These open label gains lagged slightly the gains made by patients originally randomized to 8 weeks of active pagoclone (5 months total exposure). For those patients randomized to pagoclone in the double- blind phase, the mean reduction in percent syllables stuttered was 18%, while in the open label phase, the mean reduction was 40%.

Similarly, data for the Clinician's Global Impression of Improvement (CGI- I) showed considerable gains during the three months of open label treatment........
Superficially good results. But I am a bit suspicious due to this relevant quote later in the press release:
More than 70% of the 119 patients who entered the open label phase of the EXPRESS trial were included in the three month open label data being presented at NCDEU.
In effect, 30% of the people decided to discontinue the use of Pagaclone. I would not be surprised that only the people who had a positive effect continued, so it is not surprising at all that there was at "least double the magnitude seen in the initial 8 weeks of double-blind treatment"? And most importantly, should you not actually evaluate all the patients after the 3-month open label, even those that did not take part to see the overall efficacy of Pagaclone?? Their statement of improvements is a bit misleading, because they only mention much later that only 70% took the open-label invitation up.

Thursday, June 14, 2007

New Pagaclone results are out!!

Indevus today announced some further results of the Phase II pagoclone trial, along with some results from the 3-month open label period (after the 8-week initial double-blind trial), see here. More later.

Thursday, June 07, 2007

Be a guest blogger!

This is an invitation to all the readers of TheStutteringBrain to be a guest blogger. If you feel you have an interesting idea, want to raise an issue, discuss a research paper or had an interesting experience, please email me at tom DOT weidig AT gmail. I only require that the topic of your post is vaguely related to the science/research theme of my blog, namely to Sharing with you the on-going revolution in the understanding of Persistent Developmental Stuttering.

Tuesday, June 05, 2007

Sandra Merlo as guest blogger (I)

I am happy to present Sandra Merlo from Brasil as The Stuttering Brain's first guest blogger. It is her talk at the ISA conference on Personal and professional experiences:

My stuttering started between 3 and 4 years old. It was near when my brother was born, so my parents concluded “I was jealousy and I wanted attention”. Some years later, my brother and a cousin also started stuttering and my family concluded they were imitating me. The fact was that stuttering affected several members of my family. From this fact, I had my first wrong lesson: stuttering could be learnt from imitation.

I remember that when I was 6, I already had well established strategies of avoidance (speaking less, changing words, changing phrases, not speaking with some people and so on). Even so, I could not hide stuttering all the time no matter how hard I tried. But my mother repeatedly said I was not trying hard enough, because if I really wanted I would get it. The fact was that I could not control stuttering. From this fact, I had my second wrong lesson: I did not have enought will-power.

When I was a child, I also realized that my stuttering was better in some days, with some people and talking about some topics. The fact was that I realized my stuttering had an oscillation. From this fact, I had my third and fourth wrong lessons: stuttering should be psychological and if sometimes I was better, if I tried hard enough, I could always be better.

When I was a child, I also noticed my family, teachers and friends almost never talked about my stuttering. The fact was that there was a great silence about stuttering. From this fact, I had my fifth wrong lesson: stuttering should be a so shameful thing since no one talked about it.

When I was 10, my Portuguese teacher said I had to go to a “speech-language pathologist” (SLP). I had never heard this expression before. I did not know what a SLP did. I told my mother I would like to go to a SLP, but she remembered me my pediatrician has already explained that I just had to repeat fluently what I said stuttering. According to my pediatrician, if I did this, I would be cured from stuttering. The fact was that I had wrong professional advice. From this fact, I had my sixth wrong lesson: I did not need a therapy because I could overcome stuttering all by myself.

When I was 14, I was in a great suffering, suffering entirely alone, feeling very imcompetent and with absolutely no hope. So, I decided to commit suicide.

(To be continued…)

Sandra Merlo as guest blogger (II)

But then, my English teacher realized I needed help and, for one year, he constantly talked about my qualities and my future in our classes. So when I was 15, I decided to be a SLP, because I desperately needed to understand the world I was living in.

I was admited at University of São Paulo, one of the best universities in Brazil. For the first time in my life, I had a positive consequence from my stuttering: my personal experiences with stuttering provided me with a great background to understand scientific knowledge in my years of SLP School (1997-2001). Scientific knowledge quickly made sense. At the same time, I did speech and psychological therapies.

Afterwards, I was admited to State University of Campinas, also one of the best universities in Brazil. I got a Master’s Degree of Linguistics (2003-2006), studying periodic cycles of hesitation phenomena in non-stuttering subjects. At this moment, I am attending a Doctoral Degree of Linguistics at the same university and I am studying periodic cycles of pause and the relation between hesitation phenomena and pause in non-stuttering subjects.

I have also worked at the clinical division of a SLP company, giving assistance just to patients with stuttering. My patients displayed two major characteristics: they usually needed differential diagnosis (especially regarding to cluttering, motor and vocal tics, dystonia, obsessive-compulsive disorder and attention deficit hiperactivity disorder) and they have usually done several previous therapies without success.

Last year, I got involved in Brazilian Fluency Institute, a non-profit association devoted to fluency and its disorders (stuttering, tachylalia and cluttering). Some of our actions include: the organization of the Brazilian campaign of International Stuttering Awareness Day, a great participation in the media to talk about stuttering, information and advice about fluency and its disorders, legal advices about stuttering and supervision on research.

So, now, after SLP School, Linguistics School, clinical practice and Brazilian Fluency Institute, I think I have more reasonable answers for my childhood wrong lessons.

(To be continued…)

Sandra Mello as guest blogger (III)

When I was a child I used to think stuttering could be learnt from imitation, but scientific knowledge presents evidence that, instead, stuttering may be caused by an hereditary factor or by a brain lesion (Alm, 2004; Drayna et al, 1999; Ludlow & Loucks, 2003).

When I was a child I also used to think stuttering should be the result of psychological problems, but scientific knowledge offers evidence that stuttering may be the result of basal ganglia (BG) disfunction (Alm, 2004, 2005; Ludlow & Loucks, 2003; Molt, 1999). In this case, BG would sometimes fail to generate commands to finish some sounds or syllables. This is exactly what I feel in my speech: I feel I start saying a sound/syllable and get stuck on it. This is also the way my patients usually describe their stuttering.

When I was a child I realized stuttering level had an oscillation and I thought I could control this. I did not know waxing and waning periods are intrinsic to the BG disorders and that this cannot be controled. I used to think that if I tried hard enough, I could always be with a good fluency level.

When I was a child I also used to think I did not have enought will-power, because I could not always hide my suttering. Scientific knowledge offers evidence that BG functioning is not under voluntary control. So, as a consequence, stuttering is not under our voluntary control.

If psychological problems do not cause suttering, what is the role of emotions in stuttering? I think Per Alm (2004) hits the nail on the head when he says the level of freezing response can explain emotional influences on suttering. The freezing responde occurs when the person antecipates an unpleasant situation with regard to stuttering that is going to happen and he/she does not know the best way to act and he/she does not decide fight or flight.

When I was a child I also used to think stuttering should be a so shameful thing since no one talked about it. In Brazilian society, stuttering is understood as a minor problem of minor people. I think because of this very few people and very few professionals are interested on stuttering.

Finally, when I was a child I also used to think I did not need treatment because I should be able to overcome stuttering all by myself. But this is really not the case: according to my experiences as a PWS and as a SLP, professional help is amost always necessary. Nowadays, we have at least three ways of professional help: speech therapy, pharmacological therapy and/or psychological therapy.

I used to blame myself for my stuttering, I used to blame my parents for not conducting me to a specialized treatment when I was a child, I used to blame my pediatrician for wrong professional advice, I used to blame my destiny… But, when I was 15 and I decided to be a SLP, I realized this was not a good way. I realized I could try to do something useful from my experiences: I could try to understand stuttering, I could try to improve my speech and I could try to help other people. At least try.

Monday, June 04, 2007

What is a cure?

Here is my cure level ranking.

Cure Level 4: relatively fluent but massive avoidance.
Cure Level 3: noticeable but not severe disfluency with only minor avoidance.
Cure Level 2: relatively fluent and minor avoidance.
Cure Level 1: no stuttering signs and no avoidance.
Cure Level 0: fluent without thinking and no tendency for relapse.

My statements for the day:

1) I give preference to less avoidance at the cost of less fluency.
2) Nearly everyone can be at level 1, 2 and 3 after therapy.
3) Most slowly fall back to level 3 and 4 sometime after therapy.
4) No-one ever reaches Level 0 fully.
5) Level 2 is realistic with hard work, and patience.
6) Depending on the severity, some people can reach a higher level more easily.

New evidence for basal ganglia theory?

Here is a new article published in Brain & Language on new evidence that the basal ganglia is involved in stuttering. Giraud AL, Neumann K, et al. report:

This fMRI study reports a correlation between severity of stuttering and activity in the basal ganglia and shows that this activity is modified by fluency shaping therapy through long-term therapy effects that reflect speech production improvement. A model of dysfunction in stuttering and possible repair modes is proposed that accommodates the data presented here and observations previously made by us and by others.

I write more once I have a copy for the article.