Stuttering, Movies, and Research

An interesting article appeared in the February 26 issue of the New York Times apparently stimulated by the movie, "The King's Speech.". The URL is:

http://www.nytimes.com/2011/02/26/us/26stutter.html?ref=todayspaper

Entanglement of Dopamine, Serotonin, and GABA Systems

The dopaminergic, serotonergic and GABAergic systems in the brain tend to be interrelated in a relatively complex way. Atypical antipsychotics, designed to reduce dopamine (DA) activity, are known to affect serotonin (5-HT is the abbreviation of the chemical name for serotonin) receptors while serotonin selective reuptake inhibitors (SSRIs) affect DA and GABA levels.

We have already discussed in a previous post (see the post, "Antidepressants May Affect Stuttering") the impact of SSRIs on synaptical DA levels due to the highjacking of DA transporters (DATs). In this post, we try to unravel the role of 5-HT and its somewhat confusing relationship to both DA and GABA activity.

In particular, we are concerned with the role of the different 5-HT receptor subtypes in the control of DA activity in different areas of the brain that may affect fluency. Some of the evidence presented here is derived from in vivo (i.e., within a living organism) and in vitro (i.e., external to the living organism, for example, tissue in a laboratory vessel) animal studies. Keeping in mind that caveat, the results are generalized to the human brain.

From previous posts (see posts on "An Anxious Mind Affects Stuttering"), we recall that the substantia nigra (SN) is part of the DA pathway that involves the dorsal striatum which affects motor function. The ventral segmental area (VTA) is part of the mesolimbic system involving also the ventral striatum and the amygdala associated with the emotional aspects of the mind. Both of these DA pathways contribute to stuttering--the part of the brain governing motor function and the mesolimbic system (with inputs from the environment) generating the mind state associated with anxiety.

In what follows, the various 5-HT receptor subtypes are characterized by "5-HTxy" where x is an integer and y is an alphabet. The effect of 5-HT binding to the various 5-HT receptor subtypes as gleaned from the scientific literature is different for each of the subtypes.

In the motor neuron region of the brain, 5-HT1A receptors activate DA neurons in the SN but inhibit DA neurons in the dorsal striatum. 5HT-1B receptors slightly inhibit DA neurons in the SN, while 5-HT2C receptors play no role in the DA system of the SN.

In the mesolimbic system, 5-HT1A receptors activate DA neurons in the VTA and 5-HT2A receptors enhance DA release, while 5-HT1B receptors inhibit the release of GABA in the VTA, thus contributing to further DA activation. On the other hand, both 5-HT1C and 5-HT2C receptors inhibit the DA system originating in the VTA. The majority of receptors in the VTA are of the 5-HT1B type, while there is a moderate number of 5-HT1C and an even smaller number of 5-HT1A and (the varieties of) 5-HT2 receptors.

The effects of 5-HT on DA activity obviously would depend upon the relative densities of 5-HT receptors in the different areas of the brain and these densities might differ substantially among different individuals. But it would appear, on the average, that the net effect of 5-HT binding (as well as DAT highjacking by 5-HT) in the mesolimbic and the motor neuron regions of the brain may be to increase their DA activities, neither of which would be beneficial toward the improvement of fluency.

An Alternative to The King's Speech

I was surprised to discover that there was a earlier portrayal of King George VI in a 2002 film entitled "Bertie and Elizabeth" starring James Wilby, Juliet Aubrey, and Alan Bates.  The film begins a bit earlier prior to the marriage of Albert and Elizabeth.

Albert's speech problem is portrayed in this film as less severe than in "The King's Speech."  He comes off as mostly fluent in "ordinary" conversation but blocks in stressful or conflicted situations, for example, when talking to his stern father, when giving the speech at the racetrack, and when trying to refer to Mrs. Simpson in crude terms.

As portrayed in this film, I would rank his brain involvement as at worst a 3 on a scale of 1 to 10 and his mind involvement as perhaps a 7, i.e., the physical problem (too much dopamine) is relatively mild but he is fairly reactive to his physical problem (see the post on "More on Mind/Body Problem"). 

More on Proposed Pagaclone Trial Analysis

In this post we look at enhancements to the models for pagoclone trial analyses discussed in the previous post.


For the logarithmic models in equations (2) and (3), the possibility exists that some trial participants will have become perfectly fluent, so that the after trial disfluency measure, DFA, will equal zero for these individuals. In this case the logarithm of DFA (or DFA/DFB) is undefined (going to minus infinity). One way to handle this problem is to replace DFA on the left hand side of equation (2) by (1+DFA) and then proceeding with the regression analysis.

Another approach to this problem would be to consider a logistics functional form,namely:

DFA/DFB = g * (exp(Z)/(1+exp(Z)) + e                                                           (4)

where g is another parameter to be estimated and, for example,

Z = a + b*DFB + c*T + d*SUG                                                                       (5)

An alternative form for Z could instead involve the natural logarithms of DFB and SUG. The parameters a, b, c, d, and g in equation (4) can be estimated by means of a non-linear regression analysis.

If DFA were always less than or equal to DFB then we could set g=1 on a priori grounds. However, we must consider the possibility that for some participants the level of disfluency at the end of the trial might be greater than before the trial. This situation could occur if the treatment actually had a negative effect on fluency for some individuals or perhaps, in some cases, the positive effects of the treatment are overwhelmed by naturally occurring fluctuations in disfluency.

We indicated in the previous post that nonlinear terms might be introduced into the analysis. One such term that might be of interest would be an interaction between the treatment term, T, and the level of disfluency before treatment, DFB. Then equation (2) in the previous post would become:

ln(DFA) = a + b*ln(DFB) + (c + h*ln(DFB))*T + d*ln(SUG) + e                        (6)

where h is another parameter to be estimated, and the coefficient associated with T, namely, c+h*ln(DFB), is no longer constant but depends on the level of disfluency measured before the trial.

The addition of this nonlinear term (assuming that h is shown to be significantly different from zero in the regression analysis) implies that the percentage reduction of disfluency, namely (1 - DFA/DFB)*100, due to pagoclone depends on the initial level of disfluency. For example, an individual with a greater level of disfluency at the start of the trial may show a lower reduction of disfluency at the end of the trial, or vice versa, depending on the value of the parameter, h.

Other hypotheses regarding the introduction of nonlinear terms could also be considered as well as the addition of other explanatory variables. Regression analyses of the kind suggested in the last two posts may materially contribute to a better understanding of the efficacy of drug treatments for stuttering and the impact of these treatments as a function of the individual's characteristics.

(Copyright 2011)

A Proposal for Analyzing Pagoclone Trials

A typical medical trial to test the efficacy of a treatment involves two groups--the treatment group and the placebo group, the members of which are assigned randomly.  The objective is to see if a response variable, i.e., treatment outcome, is different between the two groups. Analysis of variance (ANOVA) methodologies provide statistical tests as to whether or not the means of the two groups are significantly different.

This approach regards each group as a unit of observation and requires looking at the average of the responses within the two groups. The hope, when using grouped averages, is that the random assignments of individuals to the groups will have made all of the averages (as well as the standard deviations and higher order moments) of other possibly relevant explanatory variables essentially equal across the two groups. When the populations of the groups are relatively small, this assumption may not be valid.

Furthermore, grouped data analyses may obscure relationships that can be delineated when, instead, individuals within the groups are viewed as the units of observation. In addition, ANOVA methodologies are not able to handle very well the inclusion of many other variables (particularly those that are continuous) that may also explain response outcomes.

We propose an alternative approach based on regression analysis, which is utilized extensively in fields like economics, but very little in medical research. Regression analysis can be regarded as a supplement to ANOVA techniques to extract additional information from the individual data that may be hidden by grouping the data.

The regression model discussed below explicitly teases out the placebo effect as measured by a suggestibility variable. Consider a pagoclone trial consisting of N individuals in the treatment group and M in the placebo group for a total participation of N+M individuals.

Let DFB be the value of a disfluency measure for an individual before treatment (with either pagoclone or the placebo) and DFA the value of the measure after treatment. For example, DFA and DFB might be the results from the Stuttering Severity Instrument. Further, let SUG be a measure of suggestibility for an individual at the start of the trial, which can be constructed, for example, from the MISS questionnaire discussed in the last post. Define a dummy variable T such that:

T = 1 if the individual received pagoclone
   = 0 if the individual received a placebo.

Then a regression model describing the treatment outcome might be specified as:

DFA = a + b*DFB + c*T + d*SUG + e                                                           (1)

where a, b, c, and d are parameters to be estimated and e is an error term. The error term includes all possible explanatory variables that may have been excluded from the model and errors in the measurement of DFA as well as of each of the explanatory variables.

The model parameters can be estimated on the basis of the observations from the N+M individuals using any of a number of statistical analysis packages supporting regression analysis. The error terms for each of the observations are used to calculate a measure of goodness of fit, namely R-squared, which ranges between 0 and 1 where 1 represents a perfect fit to the data and 0 represents no fit. The parameter estimates will each have associated standard errors that can be used to calculate significance levels for the parameters.

The model can be expanded by including nonlinear terms (and additional associated parameters) such as DFA-squared, SUG-squared, DFA*SUG, and T*SUG. Moreover, if the trial involves different dosages of pagoclone, we can take that into account by adding additional dummy variables. For example, if pagoclone is administered in two different dosages, then we utilize two dummy variables, T1 and T2 defined by:

T1 = 1 for pagoclone at level 1 dosage
     = 0 otherwise
T2 = 1 for pagoclone at level 2 dosage
     = 0 otherwise

So for (T1, T2), level 1 dosage is represented by (1, 0), while (0, 1) represents level 2 dosage, and (0, 0) refers to the placebo group.

An alternative model incorporating the explanatory variables in equation (1) is a log-log model expressed as:

ln(DFA) = a + b*ln(DFB) +c*T + d*ln(SUG) + e                                                    (2)

where ln is the natural logarithm. Nonlinear terms can also be introduced into this model. Once the parameters of log-log model are estimated, we can rewrite the model as:

ln(DFA/DFB) = a + (b – 1)*ln(DFB) + c*T + d*ln(SUG) + e                                   (3)

where we used the property of logarithms that ln(DFA/DFB) = ln(DFA) – ln(DFB). The percentage reduction of disfluency is given by (1 - DFA/DFB)*100.

Regression analyses of the kinds discussed above may contribute to the specification and validation of suggestibility measures that would be useful in identifying trial participants who may be strongly responsive to placebos. This information can then be used to develop treatment trials that utilize limited resources more efficiently.

(Copyright 2011)

Placebos, Suggestibility, and Hypnosis

In a twist on the use of placebos, a study was conducted with patients experiencing irritable bowel syndrome (IBS). They were explicitly ingormed that they would be receiving a placebo and it was suggested that the placebo had been shown in the past to relieve IBS symptoms through the mind-body healing process. The bottles containing the sugar pills were labeled "Placebo."


IBS is a disorder of the lower intestinal tract involving abdominal pain and abnormal bowel movements, and emotional stress or mood disorders, such as anxiety or depression, often make the symptoms worse.

Based on a self-reported questionnaire, the placebo group indicated significantly better pain relief and reduction in the severity of other symptoms compared to those who received routine treatment. The conclusion was that communication of a positive outcome was a factor in the effectiveness of the placebo and the suggestibility of the trial participants played a role.

Reports on the study can be found at the following URLs:

http://www.nytimes.com/2010/12/28/health/research/28perceptions.html?_r=1&ref=health

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015591

Ailments that involve subjective judgments by the patient such as "how do you feel" for depressive patients or "rank the intensity of your pain" for IBS sufferers tend to be particularly amenable to placebo treatments. In the case of stuttering, evaluations of treatment efficacy for relieving symptoms may be a bit more objective. A third party (neither treater nor treated) can, for example, count the number of disfluencies normalized on some word count or speaking time scale.

Nevertheless, since we have previously argued that stuttering is basically a mind-body problem, with a substantial mind contribution, we might very well expect that results of an "open knowledge" placebo trial for stutterers might have similar results as that for the IBS study.

On the other hand, some participants in the pagoclone trials have reported that their fluencies had deteriorated during periods when they (thought they) were switched to the placebo treatments. While these periods of disfluency might be attributed to fluency variations while they were on pagoclone, I would prefer to give the benefit of the doubt to the pagoclone trial participants at this point in time until the results of the trials are published. If, for example, previous periods of greater disfluency lasted typically for days or weeks, while the placebo was administered for months (during which disfluency persisted), then this would be evidence that the disfluency was attributable to the cessation of pagoclone treatment.

The world can be divided into two types: Those who are suggestible and those who are not. More accurately, the characteristic of suggestibility may lie on a spectrum--individuals are suggestible to varying degrees. The placebo response is thought, at least in part, to be based on individual differences in suggestibility. Those who are suggestible may be more responsive to medical treatments (real or placebo) on the basis of patient belief in addition to a possible physiological mechanism. If this is the case, then controlled double blind trials of medical treatments could be improved by either controlling for suggestibility or, in the extreme case, eliminating highly suggestible individuals from the trials through prescreening.

The personality characteristic of suggestibility may be difficult to measure objectively. However, the ease with which an individual can be hypnotized as well as the depth of the hypnosis might be taken as a proxy for suggestibility, although evaluating "hypnotizability" might be a relatively subjective endeavor.

The Mental Measurements Yearbook does not indicate the existence of any psychological tests for the personality characteristic of suggestibility. However, the Multidimensional Iowa Suggestibility Scale (MISS), recently developed by Kotov, R.I. et al, is a self-reporting questionnaire that attempts to get at various dimensions of suggestibility. The questionnaire can be found at the following URL:

http://www.stonybrookmedicalcenter.org/system/files/MISS_FINAL_BLANK_0.pdf

The results from this questionnaire might be biased for individuals who have read this post and who would prefer to convince themselves or a clinician that they are not suggestible.

Communication Impacts of Stuttering

We have previously discussed stuttering in terms of its impact on fluency-- namely the smoothness and flow with which sounds, syllables, words and phrases are joined together when speaking. Fluency relates to the mechanics of speech and the ease/rapidity of oral verbal expression. Fluency enables an individual to deliver informational content quickly and with the appearance of expertise. Stuttering, on the other hand, is characterized by breaks in the fluidity of speech in addition to the repetition of parts of speech and, as such, represents a breakdown in the ability to communicate.


We can view interpersonal oral communication as consisting of two parts--namely content (what you say) and style (how you say it). Content involves purely the non-emotional information contained in the words being uttered while style involves the emotional information that is conveyed while speaking.

Consider a fluent person trying to give an oral presentation while juggling three balls in the air. Assuming that the individual does not have a high degree of proficiency with the mechanics of juggling, he may experience difficulty in concentrating on the presentation. This is exactly what happens to a stutterer who has to struggle with the mechanics of talking and is less able to focus on content as well as style.

Stuttering affects the ability, while speaking, to be articulate. Being articulate relates to the mental fluidity in the formulation and expression of thoughts, concepts, and ideas with clarity, eloquence, and effectiveness. Disfluency may hinder the train of thought, impinging negatively on formulation. One's brain in organizing thoughts generally runs faster than one's mouth. However, when one's mouth runs appreciably slower than one's brain, as with stutterers, then the ability to formulate thoughts with clarity during oral communication may be adversely affected.

Communication involves certain nonverbal elements such as voice quality, emotion and speaking style (i.e., paralanguage) as well as rhythm, cadences, intonation, emphases, and stress (prosodic features). These elements, which contribute to style (i.e, emotional content), may be affected by stuttering. The energy devoted to the mechanics of speaking substantially diminishes focus on these non-verbal elements. In addition, halting speech will certainly affect the prosodic features, namely the rhythm, cadence, and intonation of speech, which may distort or effectively eliminate expression of the communication's emotional content.

The social development of a disfluent individual may be adversely affected in the formative years during adolescence and young adulthood. In this time period, social interaction is very important for the formation of personality as the young person experiments with various identities and behaviors. Communication with his or her peer group is very important at this stage. Unfortunately, a person who stutterers may not get much out of this development stage, since his attention may be focused on the mechanics of speech, he may be ostracized somewhat by his peer group, and the disfluency may severely limit his communication capabilities in terms of both content and style. The normal give and take of conversation during which ideas and concepts are bandied about and the ability to think on the fly in the course of a conversation may not be cultivated in a person who stutters.

Given all of these impacts of stuttering, an individual experiencing this ailment in addition to being less fluent, might also be expected to be less articulate and socially skilled.

Endogenously Reducing Dopamine

An interesting article in Time magazine (January 12, 2011) regarding the enhancement of cognitive performance discussed the use of Adderall (a stimulant) to improve cognitive performance by increasing levels of dopamine. However, it was found that there was no statistically significant difference in cognitive performance of Adderall relative to a placebo, suggesting that you can get the same dopamine boosting benefits of the drug by believing you will do well which itself releases dopamine. This is an example of the mind coming into play to influence bodily functions (in this case, cognition which is a function of the brain).


In a previous post (Parkinsons Disease, Dopamine, and Stuttering), we pointed out that patients suffering from Parkinsons disease who received a placebo showed a substantial increase of dopamine activity according to brain imaging results. So we speculated that a nocebo-like effect of context on stuttering might also increase the level of dopamine activity in the brains of stutterers, thus negatively affecting their fluency.

We can turn this argument around and ask whether or not a placebo, which could be an endogenously influenced state of mind, might reduce dopaminergic activity and hence improve fluency. This endogenous mind state might be produced solely by the individual himself through some sort of mental manipulation.

Consider the case of King George VI as depicted in the film, The Kings Speech.  We should not automatically assume that the success of King George VI in giving his wartime speech with relative fluency was due solely from fluency shaping techniques and modifications in the mechanics of his speech suggested by his therapist. We should also consider the possibility that he harnessed his mind in such a way as to generate a placebo-like effect whereby the dopaminergic activity in the relevant parts of his brain actually decreased. Granted, the king had a cheerleader in the form of his therapist (who may be regarded as an exogenous influence), but nevertheless we must consider the possibility of purely endogenous influences as well.

There are anecdotal reports of individuals achieving similar effects--namely the attorney who was fluent in a professional setting but would stutter with friends and family, and the college professor who claimed to be able to "psyche himself up" prior to teaching a class through some sort of mental preparation so as to lecture fluently. The mechanisms by which this happens are obscure and resistant to simple codification such as "pop this pill one hour before..." The "buttons" that are pressed and the "switches" that are flipped in the mind to activate the "internal cheer leader" and to achieve these feats are unknown. Yet, consider the possibility that it could be done by some individuals.

The manipulation of dopaminergic activity through endogenous brain states might be comparable to the modification of the neurotransmitter endorphin levels claimed by practitioners of meditation techniques. But with meditation, there exists a well codified regimen, if practiced leads to the desired results.

It is not clear whether all stutterers can control their fluency by manipulating their endogenous mind states or if this approach is limited to a subset based perhaps on the intensity of the underlying physical cause of stuttering (rated on a scale of 1 to 10). It may be that only those individuals with relatively mild physical causes of stuttering (and presumably lower dopaminergic disfunction) can achieve fluency by endogenously manipulating their mind states.

Serotonin, Dopamine, and Stuttering

As in the previous post, which raised the possibility that viruses cause stuttering, this post again addresses the question as to what might be the root cause of excessive dopaminergic activity.


Reiterating the discussion in the post entitled "Antidepressants May Affect Stuttering," SSRIs inhibit the reuptake of serotonin by presynaptic neurons permitting greater concentrations of serotonin in the synapses. Excessive serotonin concentrations may highjack dopamine active transporters (DATs) prohibiting them from doing their job of dopamine reuptake. Consequently, synaptical concentrations of dopamine may be higher, leading to disfluency.

Now consider the possibility that some stutterers might have excessive levels of naturally occurring synaptical serotonin (i.e., independent of whether or not they take antidepressants). This may be the result of a low density of SERTs to reuptake serotonin or of the brain's overactive production of serotonin. At any rate, such a situation might lead to the highjacking of DATs resulting in less reuptake of dopamine, greater concentrations of dopamine, and greater disfluency. If this were the case, we might consider selective serotonin reuptake enhancers (SSREs) to reduce the levels of serotonin.

Independent of whether or not they take antidepressants, some individuals may have lower densities of DATs in the brain impairing its ability to reuptake dopamine, again leading to higher concentrations of dopamine and, hence, adversely affecting fluency. So we might consider the possibility of a class of drugs which we could call dopamine reuptake enhancers (DREs) that would reduce the levels of dopamine in the synapses by making the DATs more efficient with respect to dopamine reuptake.

Are there drugs that are reuptake enhancers?  With respect to the reuptake of dopamine, I am unaware of the existence of any such drugs. The only known drug that enhances the reuptake of serotonin is tianeptine. Tiapentine has low affinity for SERTs, so its effect on serotonin reuptake appears to be indirect. Newer research seems to indicate that tiapentine acts through some downstream mechanism that is not yet fully understood.

What the discussion above illustrates is that the relationships among neurotransmitters and their effects on the brain are very complex. There are interrelationships among the various neurotransmitters and these connections are currently not fully understood by the research community. Given the relationships among the dopaminergic, GABAergic, and serotonergic systems we have thus far seen, the obvious explanation of excessive dopamine as the root cause of disfluency may be overly simplistic.

Moreover, stutterers may fall into various subgroups, for example, characterized by excessive serotonin production, low SERT densities, insufficient DAT activity, other inadequacies of the dopaminergic or GABAergic systems, etc. And the appropriate therapeutic drug treatments to get at the root source for these different subgroups may not be the same.

In future posts, we will further discuss relationships between the serotonergenic and dopaminergic systems

No Amygdala, No Fear

An interesting article in the NY Times discusses a woman without an amygdala. The article can be found at:

http://nyti.ms/fnHMHh

Essentially,the woman has no fear. So one wonders if a stutterer with a similar condition would only exhibit primary stuttering as discussed in the posts on the "Anxious Mind."

Antidepressants May Affect Stuttering

Antidepressants such as Prozac, Zoloft, Celexa, and a host of others are known to affect levels of the neurotransmitter serotonin in the brain alleviating depression.. But the question is: How might they affect stuttering?

Antidepressants are selective serotonin reuptake inhibitors (SSRIs), which means that they:

     - reduce reuptake of serotonin into presynaptic neurons
     - increasing serotonin concentrations in the synapses between the pre- and post-
       synaptic neurons
     - encouraging uptake into the post-synaptic neurons.

(see the August 25, 2010 post entitled "Stuttering and Neurons" for a graphical depiction of the workings of neurons)

In this way, SSRIs allow serotonin to perform its task as a chemical messenger enabling neurons to trigger nerve impulses in neighboring neurons, which presumably reduces symptoms of depression.

However, recent research has raised the possibility that SSRIs may have a more complex effect on neurotransmission. Reduction of depression may result also from SSRI's activation of the dopaminergic system in addition to the serotonergic system.

SSRIs prevent reuptake of serotonin by inhibiting the action of serotonin transporters (SERTs). These are molecular cargo carriers that recycle serotonin back neuronal storage sacs called vesicles located on presynaptic neurons.

But in addition to SERTs, there also are dopamine transporters (DATs) that are involved in a similar fashion with dopamine reuptake. Increased DAT activity has been associated with clinical depression since they act to reduce the levels of synaptic dopamine. Normally DATs exhibit a low affinity for serotonin, but higher serotonin levels lead to the uptake of serotonin by DATS. In this way, the DATs are effectively highjacked by higher serotonin concentrations and cannot function as "dopamine absorbers" leading to

       - less reuptake of dopamine by the presynaptic neurons
       - greater concentrations of dopamine in the synapses
       - enhanced dopamine uptake into postsynaptic neurons

This enhancement of the dopaminergic system reduces the symptoms of depression. The relatively inefficient and slow process of the hijacking of DATs by serotonin may explain why it takes weeks before anti-depressive effects are observed during SSRI treatment.

But while enhanced dopaminergic activity may be beneficial for relieving depression, it might not be appropriate for improving fluency if the dopaminergic hypothesis of stuttering is correct. Among stutterers using antidepressants there have been reports of greater disfluency. although, to my knowledge, no large scale studies regarding the effects of antidepressants on fluency have been conducted.

Can Viruses Cause Stuttering, Part 2?

If the viral hypothesis were correct, then the therapeutic treatment of stuttering would be drastically modified. In particular, anti-infective agents might be administered to tamp down any infection that may arouse an implicated retrovirus or to attack the retrovirus directly. One of the approaches that is being taken for schizophrenia is to indirectly neutralize the HERV-W retrovirus using the drug artemisinin. And in the case of multiple sclerosis, an antibody is being tested that attacks a primary virus protein.

In addition, the identification of prenatal care strategies or postnatal vaccinations could prevent infections that might put individuals on the path to stuttering. Infections in the mother prior to an infant's birth may put the infant into a high risk category. In which case, these infants might be identified and receive an appropriate therapeutic treatment to forestall the onset of stuttering.

I am always amazed at the glacial progress in medicine. Aside from relatively rare serendipitous discoveries that lead to punctuated advances of medical knowledge/treatment, the accretion of understanding of many ailments' causes and their treatment is a tediously slow process. For example, not too long ago, hemochromatosis--too much iron in the blood--killed people. And the remedy, when it was found involved something as simple as draining blood (e.g., by the use of leeches).

And so it is regarding the understanding of the causes and possible treatments of stuttering. Only recently was the dopamine hypothesis of stuttering taken seriously even though it was first put forward in the 1930's.

I suspect that any testing and/or acceptance of a viral hypothesis for stuttering might likewise be a protracted process. But if the current research concerning schizophrenia and multiple sclerosis bears fruit, then there will be impetus for examining other neurologically based ailments such as stuttering.

Granted it is very difficult to identify viruses or viral infections and associate their presences with specific medical problems as the Discovery magazine article attests. Nevertheless, it might be useful to engage in large scale epidemiological studies to identify correlates with stuttering. Epidemiology is the study of patterns of health and illness and associated factors at the population level. It informs evidence-based medicine in order to identify health care risk factors, approaches for preventative medicine, and optimal treatment regimens.

An epidemiological study of stuttering would involve both the collection of medical histories of people with this infliction as well as appropriate blood/bodily fluid/tissue samples. In addition, both functional and structural brain imaging should be conducted for a substantial proportion of subjects.

The idea behind an intensive epidemiological study would be to contribute to a causative theory of stuttering, to identify possible subgroups of stutterers, and to develop therapeutic approaches based on any new knowledge.

Can Viruses Cause Stuttering, Part 1?

In previous posts, we discussed the dopaminergic hypothesis of stuttering, i.e., that the root cause of stuttering may be excessive dopaminergic activity in the basal ganglia area of the brain. We can now ask what might be the root cause of the abnormal dopaminergic activity. Many think that it may be a genetic cause--through inheritance or through an unlucky throw of the genetic dice, stutterers have a faulty genetic system that expresses itself as excessive dopaminergic activity.

But there may be an alternative explanation. An intriguing article in Discover magazine raises the possibility of a virus being the root cause of other neurological diseases such as schizophrenia, bipolar disorder, and multiple sclerosis. The website for this article can be found at

http://discovermagazine.com/2010/jun/03-the-insanity-virus/article_view?b_start:int=3&-C=

Much like stuttering, imbalances of dopaminergic activity have been observed in the brains of individuals suffering from schizophrenia, but this abnormal activity occurs in a different combination of the brain's anatomical regions. And until recently schizophrenia was also thought to result from bad genes.

The Discover magazine article raises the possibility that schizophrenia begins with an infection. Many schizophrenics show chronic inflammation with respect to their infection-fighting white blood cells. Moreover, they often carry antibodies resulting from viral infections but not the viruses themselves, suggesting that they had been exposed to those infectious agents at some earlier point in their lives.

Viruses are not necessarily passed from person to person by bodily fluids or other contact. Rather, some may live permanently in the human body at the very deepest level intermingled with human DNA. Some researchers now believe that retroviruses, which are types of viruses that convert RNA into DNA, could be the culprits explaining a number of neurological ailments.

Viruses like influenza or measles kill cells when they infect them. But when retroviruses infect a cell, they often let the cell live and splice their genes into its DNA. When the cell divides, the resulting pair of cells carry the retrovirus’s genetic code in their DNA into future generations.

Although it is a rare random event, over the last 100 million years various retroviruses have gotten into human genomes by having infecting one of our animal ancestors in the evolutionary chain. About 100,000 retrovirus sequences appear in human DNA, accounting for more than 40 percent of all DNA. These retroviruses are usually tied up in tight stacks of proteins, but once in a while they slip out, switch on, and start manufacturing proteins beginning the process of infection. About 5 percent of the RNA produced in the brain arises from what appears to be “junk” DNA, which also includes endogenous retroviruses. The presence of RNA could mean that viral proteins are being manufactured in the body more frequently than previously thought since RNA is a step in the path to making proteins.

Although the body tries to keep endogenous retroviruses under control, infections can destabilize this balance. Many infections, such as herpes, toxoplasma, cytomegalovirus, and a dozen others may awaken a retrovirus. The retrovirus contains proteins that activate the immune system during these infections and the white blood cells produce inflammatory molecules called cytokines that attract more immune cells generating a cascading effect.

Whether people develop a specific neurological problem may depend on how their immune system responds to a retrovirus. Several studies implicate immune genes called human leukocyte antigens (HLAs) that are instrumental in the body’s ability to detect invading pathogens. The response to an infectious agent may be why one individual develops a specific neurological ailment and another person does not.

As a concrete example, human DNA has been found to have human endogenous retrovirus W (HERV-W) at specific addresses on chromosomes 6 and 7. Several studies have found active elements of HERV-W in the blood or brain fluids of people with schizophrenia (49% of schizophrenics vs. 4% of healthy people). The more of these active elements they had, the more inflammation they exhibited. In schizophrenia inflammation may overstimulate neurons. The neurons, being excited by these inflammatory signals, discharge neurotransmitters, leading to such symptoms of schizophrenia like hallucinations, delusions, paranoia, and hyper-suicidal tendencies. Some initial infection could have set off a lifelong pattern in which later infections reawaken HERV-W, causing more inflammation and eventually symptoms, explaining why schizophrenia waxes and wanes like a chronic infection.

In summary, genes may lead to a specific neurological problem only in conjunction with certain environmental kicks and a genome’s myriad of parasitical retroviruses might provide part of that kick. Retroviruses can be activated by inflammation resulting from infection and possibly even cigarette smoke or drinking water/food pollutants. In addition, we cannot rule out at this point that a stressor activating a retrovirus might be an emotional trauma affecting the immune system rather than some initial physical invasion. Since stuttering has some parallels to schizophrenia in terms of dopaminergic activity imbalances, a viral cause of this ailment should certainly be considered.

An Anxious Mind Affects Stuttering, Part 3

In this post, we continue to recast earlier posts in terms of the anxious mind perspective of the last two posts. In particular, we revisit the diagram presented in the post entitled "Parkinson's Disease, Dopamine, and Stuttering." This diagram can now be presented from a more (structurally) neurological perspective.

The node previously characterized as "Excessive dopamine activity" is replaced by "Striatum" and the node characterized as "Mind" is replaced by "Amygdala."  Anxiety is regarded as a manifestation of a hyperactive amygdala and, as such, is not regarded from this perspective as a causative factor. The striatum affects fluency by virtue of its excessive dopaminergic activity the source of which is the substantia nigra (not shown in the diagram). Similarly, the amygdala by way of the ventral segmental area (not shown in the diagram) feeds additional dopamine to the striatum further affecting fluency.

Finally, in keeping with the previous post on "Stuttering, Placebos, and Nocebos," the "Context" node is replaced by "Conditioned Stimulus." The idea here is that a previous (otherwise neutral) event/situation becomes associated with (consciously or subconsciously) an episode of disfluency; so essentially that event/situation (e.g., speaking before an audience) is a conditioned stimulus that triggers greater activity (i.e., a conditioned response) in the amygdala.

What has not been taken into account in this diagram is that secondary stuttering is qualitatively different from primary stuttering. An amygdala that becomes excited does not only change the frequency of disfluency but also leads to modifications in the nature of the disfluency (i.e., blocks vs. easy rhythmical repetitions).

From a mechanical point of view, we can understand what is happening: A child experiencing primary stuttering develops awareness of his problem and, attempting to consciously intervene, then develops secondary symptoms like blocking. The motor neuron system simply will not allow him to bypass and override the rhythmical repetitions. But from a neurological perspective, the mechanism of action is, at this point in time, not clear. So we have to limit the applicability of the diagram above to individuals already in the secondary stuttering phase.

An Anxious Mind Affects Stuttering, Part 2

In light of the previous post on the anxious mind, we reiterate and recast some of our earlier discussions regarding drugs, mind, and measurement.


First, If the dopaminergic hypothesis of stuttering is valid, reducing dopaminergic activity using, for example, atypical antipsychotic drugs may directly reduce stuttering by acting on the striatum. In addition, since the great majority of neurons in the basal ganglia utilize GABA as a neurotransmitter with inhibitory effects on their targets (namely dopamine neurons), it is no wonder that GABAergic enhancing drugs (such as BZs) also may improve fluency.

Secondly, both dopaminergic antagonistic (i.e., inhibiting) drugs and GABAergic agonist (i.e., enhancing) drugs may modulate hyperactivity of the amygdala to indirectly influence the level of dopamine in the striatum with the end result of further improving fluency.

These drugs are not localized in their effects; instead they "wash" over the brain and affect the responses of neurons in both the basal ganglia and amygdala. So, if the model of behavior discussed in the previous anxious mind post is correct, the issue concerning whether an antipsychotic or BZ medication merely reduces anxiety thus improving fluency is largely irrelevant.

In an earlier post, we argued that the brain problem leading to stuttering may be ranked on a severity scale ranging from 1 to 10. Similarly, the mind component of stuttering can also be ranked on a 1 to 10 scale.

Based on the discussion in the previous post, we could circumvent the amorphous construct of "the mind" and instead rank the hyperactivity of the amygdala on a 1 to 10 scale. We thus may have a potential method of actually measuring the two dimensions of stuttering, namely the mind and the body, by means of existing brain scan technologies.

This may be an oversimplification, but if the activity of the amygdala were measured to have a rank value of A (ranging between 1 and 10) and the striatum were observed through a brain scan to have an activity ranked with a value of S, then the independent activity of the striatum would be ranked (S-A). We subtract the amygdala's activity from the striatum's activity since the brain scan measurement of the striatum involves both the direct effect of the striatum and the indirect effect of the amygdala. The caveat, of course is whether or not existing brain scan technology can provide some meaningful and quantifiable indication of activity in the two organs and that these effects are additive in the striatum.

An Anxious Mind Affects Stuttering, Part 1

Primary stuttering is characterized by easy rhythmical repetition and prolonged sounds, syllables, or words. A young child exhibiting primary stuttering is unaware of his speech and there is no anxiety associated with this stage. Awareness of speech depends upon age and cognitive development and children at this stage are usually between 4-6 years old.

At a later age, primary stuttering generally evolves into secondary stuttering characterized by tense uncontrollable repetitions, prolongations, hesitations, and blocking. This stage is associated with anxiety with respect to one's speech.

It appears that the root cause of primary stuttering is dopaminergic overactivity in what we had vaguely referred to in previous posts the "motor neuron section of the brain." But to be more specific, that part of the brain instrumental in motor activity and whose malfunction plays a role in stuttering is thought to be the basal ganglia, a group of nuclei situated at the base of the forebrain.

The main components of the basal ganglia are the striatum, pallidum, subthalamic nucleus, and substantia nigra. In the basal ganglia, the great majority of neurons use GABA as a neurotransmitter and have inhibitory effects on their targets. However, the substantia nigra is a source of dopamine for the (dorsal) striatum. The dorsal striatum controls sensorimotor responses and excess dopaminergic activity contributes to primary stuttering.

In addition, the basal ganglia has a limbic sector (related to emotion and behavior) whose components are the ventral striatum (also called the nucleus accumbens), the ventral pallidum, and the ventral tegmental area (VTA). The VTA provides dopamine to the (ventral) striatum in the same way that the substantia nigra provides dopamine to the (dorsal) striatum.

The root source of secondary stuttering may lie in another part of the brain, namely the amygdala, an almond shaped structure nestled in the middle of the brain which communicates with the VTA. The amygdala appears to have many functions in terms of its involvement in mental states, but the one important for this discussion is its role in the anxiety/fear response.

In previous posts, we have stated that stuttering is basically a mind/body problem. The mind as a manifestation of the brain involves consciousness, awareness, thought, reason, perception, will, imagination, unconscious cognitive processes, emotional states, and temperament. The emotional state that particularly interests us here is that of anxiety and one aspect of temperament of interest is that of over-reactivity.

An interesting article in the New York Times magazine (October 4, 2009), entitled "The Anxious Mind," argues that some children may be born with over-reactive temperaments. The article may be found at the website:

    http://www.nytimes.com/2009/10/04/magazine/04anxiety-t.html?scp=6&sq=Anxiety&st=cse

Specifically, these children have lower thresholds for arousal in various areas of the brain such as the amygdala, the hypothalamus, and the hypothalamic-pituitary-adrenal axis. This latter is the circuit responsible for the stress hormone, cortisol.

Highly reactive individuals have a particular brain circuitry that leads to a hyperactive amygdala. Nerve circuits originating in the midbrain provide inputs of dopamine to the amygdala and these dopamine signals indicate the importance of a given event. Hypersensitivity of dopamine release is regarded as a biochemical marker of over-reactivity and vulnerability to stress.

The amygdala sends impulses to the nuclei of the VTA for activation of dopamine as well as other neurotransmitters. In turn, as we pointed out above, the VTA provides inputs of dopamine to the striatum, part of the basal ganglia system. In this way, the "mind" via the amygdala may contribute to disfluency over and above the primarystuttering generated directly by excessive dopaminergic activity in the basal ganglia.

Another part of the brain, the prefrontal cortex, is thought to modulate the signals of the amygdala and is implicated in emotional regulation. Individuals with thicker cerebral cortexes have been shown to have better responses to stress and anxiety. Conversely, a thin cortex may be unable to regulate excessive activity in the amygdala, leading to excessive anxiety (see the NY Times magazine article).

If primary stuttering originates from excessive dopaminergic activity in the basal ganglia, then secondary stuttering may result from hyperactivity of the amygdala, the outputs of which may not be very well modulated in some individuals having thinner prefrontal cortexes.

So, in summary, the amygdala may be implicated in the generation of a state of the mind involving one aspect of the temperament of an individual, namely that of proneness to anxiety. Whether the intensity of this trait for stutterers is an inborn characteristic (as suggested by the NY Times article) or is acquired as a result of stuttering at this point is an open question. In either case, the amygdala may affect the basal ganglia by effectively increasing its dopaminergic activity and, hence, disfluency.

Drug Dosages and Additional Drug Candidates

Dr. Maguire, UC Irvine, sent the following information regarding drug dosages for asenapine; in addition, he mentions a few other drugs that may have the potential to improve fluency:


Saphris (asenapine) has recently been approved in the EU under the trade name Sycrest. The dosage range we are utilizing at UC Irvine for stuttering are 2.5 mg to 10 mg administered at night. Asenapine does have some significant anti-histamine blockade which can lead to sedating qualities. We have not extensively studied pregabalin in stuttering but one tends to start at a relatively lower dosage in at 50-75 mg twice a day and can increase based on tolerability.


A newer dopamine antagonist, iloperidone, is now available as well. It has not been extensively studied in stuttering yet but is associated with less sedation as it has minimal effects on histamine. It does have an effect on noradrenergic alpha-1 receptors which can lead to dizziness and lowering of blood pressure. Therefore, a titration with beginning at a lower dosage and gradual increase is required. I agree with the author regarding the concern of long-term benzodiazepine use in stuttering.

We are also very excited to begin the use of lurasidone which has also been recently FDA approved for schizophrenia. We need to learn much more about this agent and its potential usefulness in stuttering.

Information regarding the clinical and research program with which Dr. Maguire is associated can be found at the following website as well as the links indicated therein:

http://uci.edu/2008/12/feature_stuttering_081124.php

Using Drugs to Improve Fluency

I received the following blog comment:
im from the uk and looking at doing experiential treatment with Saphris and Lyrica.
Any idea what doses to start with?

Saphris is the commercial name for asenapine and Lyrica is the commercial name for pregabalin.

First, even if I knew the answer it would be inappropriate to provide such advice by internet. Dosages depend upon body-mass and the individual's specific brain neurochemistry.

That said, anyone desiring to use existing prescription drugs off-label to improve fluency should, in the ideal, consult with a clinical psychopharmacologist. This may be an M.D. or a psychiatrist with advanced training in this specialty. The medical professional will also be knowledgable as to what blood or other tests you may need to monitor the effects of any of the drugs you may be taking.

Before using any combination of drugs, it is important to look for adverse drug interactions. A pharmacist may also be helpful in this regard.

Start with a single drug and build up to the recommended dose. Then do the same for the other drug taken alone. Observe the effects of the drugs when taken individually. Next, take the drugs simultaneously and vary their dosages. Hopefully, you may find some combination of drugs/dosages that work for you in the sense of improving fluency while having minimal or no adverse side effects. On the other hand you might find that the negative effects of the drugs are cumulative.

During this period, keep a journal recording the effects of the drugs on fluency as well as any side effects. Remember that while taking these drugs you may also have naturally occurring variations in your neurochemistry so you must withdraw and restart dosages periodically in order to decide if it is the drugs that are improving your fluency. Also, if you are a highly suggestible individual, the effects you observe may be placebo-based. But if this were the case, these effects should be short-lived.

If you are currently partaking in a drug trial keep to the protocol and DO NOT take any additional drugs. Otherwise, you might compromise the integrity of the trial.

Lastly, we would appreciate if you would report any results, negative or positive, to this blog site.

Further Drug Research

Dr. McGuire, UC Irvine, sent the following communication:

Endo Pharmaceuticals is still analyzing the Pagoclone IIb results and my co-investigators and I will seek publication of the data once fully analyzed. As you know, we did publish the Phase II study in the Journal of Clinical Psychopharmacology earlier this year. Also, my colleagues and I at UC Irvine will be starting a trial of asenapine for stuttering in the coming months. We have other compounds for stuttering in our pipeline development as well. Fortunately, multiple studies investigating dopamine antagonists in stuttering (e.g. haloperidol, risperidone, olanzapine) have yielded positive efficacy. Newer generation dopamine blocking agents such as asenapine and others have fewer side-effects than their predecessors and we are very excited to begin this new chapter in stuttering pharmacotherapy research.
Again, I want to thank the author of this blog for providing this forum for discussion.

We look forward to the publication of the phase IIb pagoclone trials. It is also good to hear that exploratory research is being conducted to identify other drugs that may improve fluency. We realize that therapeutic drug testing is a long and tedious process. This testing may be even more difficult in the case of stuttering because the mind plays an important role in determining outcomes which makes separating genuine effects from placebo effects challenging.

Asenapine is a member of the class of atypical antipsychotics and, as such, acts directly to block dopamine activity. It is claimed that users of asenapine have less weight gain and a reduced risk of developing diabetes, so this drug may be marginally better than Zyprexa or Abilify in that regard. However,much like with the other atypical antipsychotics, anecdotal reports indicate that some users taking this drug feel "zoned out," "zombie-like," and "groggy."
One problem with virtually all neurotransmitter drugs is that they lack selectivity with regard to the areas of the brain that they affect. Dopamine antagonists not only inhibit dopaminergic activity in the motor neuron section of the brain (which is good for improving fluency) but also in other areas of the brain which may lead to other unwanted or adverse effects. At this point in time, no obvious mechanisms for targeting a specific brain area are apparent, but this would be an interesting area for further research.

It might also be interesting to administer multiple drugs at the same time. For example, a weaker dose of an atypical antipsychotic coupled with a dose of gabapentin or pregabalin would have the effect of depressing the dopaminergic system while enhancing GABAergic activity. A potential advantage of multiple drug therapy might be that the negative aspects of a stronger dosage of a single drug may be avoided. Of course, the possibility of adverse drug interactions would need to be taken into account when using multiple drugs.

In a shortly upcoming post, we will put forth some speculations on the neurobiological basis of the mind as it affects stuttering.

Rationale for this Blog

I received this comment from an anonymous source recently.  My response is below.


Your blog seems interesting and useful. However, I'm puzzled that it seems entirely anonymous - unless I'm missing something. Personally, I'm always skeptical and suspicious of anything that's written anonymously. I think, who is this guy? What's his agenda, and what's he trying to hide? Why not tell your readers who you are and why you're writing, like a normal blog? I think you'd be better respected and more widely read, and your ideas would be more likely to be accepted.


This is not an ego-based blog and personalities and their identification are not required.  Look at this blog as a counter-weight to those blogs that slant toward an anti-drug perspective.  Unfortunately, drug therapy is just about the only game in town for the alleviation of stuttering. There are drugs currently on the market that have the potential to improve fluency.  And virtually all drugs have associated risks, but the decision to take a drug should be based on a cost-benefit analysis (in this case benefits include "negative benefits"--i.e. risks-- as well as positive benefits of improved fluency).  Hiding behind the placebo explanation when individuals report improved fluency when using, for example, pagoclone, I think, may insult the intelligences of these individuals.  Whether or not these individuals are representive of  the larger community of stutterers or are part of a smaller subgroup is currently an open question.

Proposal for Beyond Pagoclone Drug Trials

We have argued in previous posts that there may be several potential etiologies (causes) of stuttering--namely excessive dopaminergic activity, insufficient levels of GABA, or inadequate neurosteroid production. Moreover, these chemical imbalances in the brain may stem from a myriad of problems. For example, excessive dopaminergic activity may be due to the production of too much dopamine, or too large a density of dopamine receptors on post-synaptic neurons, or insufficient dopamine reuptake by pre-synaptic neurons. Similarly, in our discussion of GABAergic drugs we have seen that the level of GABA depends on a number of factors as well.


It is reasonable, therefore, to speculate that stutterers might fall into subgroups based on the potentially different underlying root causes of their disfluency. If this were the case, then we could not expect that all individuals would respond the same to any specific drug therapy. And this observation has implications for the testing of the impact of drugs on fluency.

Given that a number of different drugs have been identified that target different pathways leading to excessive dopaminergic activity, it is reasonable to propose that these drugs be put through clinical trials to test their efficacy on fluency. Since the drugs are currently on the market and used for other purposes, presumably their safety already has been established to the satisfaction of the relevant government agencies. Thus, phase 3 trials testing for safety may not be required for these drugs.

One difficulty with conventional trials is that they basically take all comers. Many participants may not benefit from a specific drug treatment and those who do not respond may cause the drug to fail even though a significant minority might benefit.

A new model, called "adaptive design," for drug trials has been applied to the treatment of breast cancer. It focuses on leaner faster trials involving simultaneous testing of multiple drugs that enroll patients with a higher probability of responding to a specific treatment. And, unlike conventional trials in which results are not examined until the end, data is examined as the trial progresses. What is learned in the early going determines which drugs are administered to specific trial participants later in the study.

This model can be adapted to the testing of drugs that may affect fluency. Unlike drugs for breast cancer where a cure is sought, fluency enhancing drugs are a palliative rather than a cure. Thus, it may even be possible to eliminate a standalone control group in such a design by cycling trial participants through periods where the drug being tested is replaced by a placebo and observing the effect on both fluency using standard methods and on dopaminergic activity via brain scans. In addition, given the existing theoretical understanding of the action of a drug, the classification of trial participants may be further refined according to their specific etiologies.

Finally, since the clinical trials would involve existing drugs from a number of commercial pharmaceutical companies, it would be appropriate that the trials be conducted by a government organization (such as the NIH), a clinical trials unit in the academic sector, or a contract research organization not affiliated with any pharmaceutical company. In this way, we could enhance the level of objectivity of any such study.

Beyond Pagoclone, Part 3

In this post we look at a couple of alternative over-the-counter supplements that have been tried as fluency enhancers. In the previous posts, all of the alternative drugs discussed require a doctor's prescription except for Phenibut.


Some stutterers have reported mildly improved fluency when taking an over-the-counter supplement 5-HTP (see www.stutteringforum.com blog). Since 5-HTP is claimed to be a serotonin activity enhancer, the question arises as to how this may come about. The answer may Iie in some research conducted by a group of Stanford University medical researchers (see Andrews et al, Journal of Neurochemistry, 1978, vol. 30, pp. 465-470; also see www.neuroassist.com/neurotransmitter-depletion-5-HTP-Depletes-Dopamine.htm). They claim that 5-HTP may be a dopamine depletor based on their studies with rats. Thus, reducing the levels of dopamine according to the dopamine hypothesis of stuttering should improve fluency. Whether or not 5-HTP has long lasting effects or has only a transient impact is an open question. To my knowledge, no controlled double blind trials have been conducted to determine 5-HTP's effect on fluency.

Vitamin B-6 has also been tried as a fluency enhancer (see blog cited above). The idea here is that vitamin B-6 is involved in the production of GABA, which inhibits the action of dopamine. But the situation is a bit more complicated than that as we see in the somewhat simplified diagram below.

Indeed, B-6, along with Glutamate and GAD (glutamic acid decarboxylase), is involved in the GABA synthesis process (denoted by the green directed lines). And GABA inhibits the action of dopamine as shown by the red directed line.  But note also that B-6 reacts with GABA along with GABA-T (GABA-transaminase) to produce succinic acid which is involved in the negative feedback inhibition of GAD (again denoted by the red directed line). In addition, we also see from the Figure that B-6, along with Dopa is involved in the production of dopamine. So B-6 has a positive effect on the production of GABA, but also a negative effect on GABA levels because of its reaction with GABA and GABA-T (producing succinic acid), and an additional negative effect by way of being involved in the synthesis of dopamine. Obviously vitamin B-6 plays a delicate balancing act in maintaining an equilibrium among different neurotransmitters except perhaps in the brains of stutterers. Based on the above discussion, it is very difficult to determine what the net effect of taking vitamin B-6 might be on the fluency of any particular individual.

Beyond Pagoclone, Part 2

This post discusses two additional drugs that may act to improve fluency.


Pregabalin, marketed by Pfizer under the trade name Lyrica, is claimed to be a more potent successor to gabapentin. Pregabalin increases GABA levels by enhancing GAD (glutamic acid decarboxylase) activity. GAD is an enzyme that converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. By this action, pregabalin also decreases the level glutamate and, in addition, decreases the excitatory neurotransmitter norepinephrine.

Pregabalin's therapeutic effect appears after about a week of use and is similar in effectiveness to BZs, but it is claimed that pregabalin produces more consistent therapeutic effects for anxiety symptoms. In addition, unlike BZs, it appears that pregabalin is effective over the long term without the development of tolerance, does not disrupt sleep patterns, and leads to less severe cognitive and psychomotor impairment. Its lower potential for abuse and dependence makes it preferable over BZs.

In addition to binding sites for GABA and BZs, GABA receptors also contain binding sites for various neurosteroids, which are produced naturally in the brain. . The transfer of cholesterol into glial cells is involved in the synthesis of naturally occurring neurosteroids such as allopregnenolone and tetrahydrodeoxycorticosterone. These neurosteroids, much like BZs, enhance the activity of GABA

An excitatory neurotransmitter such as dopamine acts as a gas pedal to use an automotive analogy, while GABA acts as a brake pedal. The level of neurosteroids, which act as a brake fluid, control how strongly the brakes (i.e., GABA) are actually applied. So increasing certain neurosteroid levels will increase GABA function, thus reducing dopamine function. In effect, these neurosteroids bind to and modulate the behavior of neuronal GABA receptors.

Neurosteroid drugs such as ganaxolone, an analog of allopregnanolone, which is a positive modulator of GABA-A receptors, may have advantages over other GABA-A receptor modulators, notably BZs, in that tolerance does not appear to occur with extended use.

In a previous post, we discussed the dopamine overabundance hypothesis of stuttering, which assumes excessive dopaminergic activity either because of an overabundance of dopamine receptors in the motor neuron section of the brain or because of excessive amounts of the excitatory neurotransmitter dopamine in this brain region. But if neither of these conditions is present, the problem might be that there is insufficient GABAergic activity, which would inhibit the dopaminergic activity. This leads us to a GABA insufficiency hypothesis of stuttering. In view of the discussion regarding neurosteroids in this post, we can posit a third hypothesis of stuttering--namely the neurosteroid insufficiency hypothesis of stuttering. Insufficiency of certain neurosteroids may lead to a weak GABAergic response which, in turn, results in an overly active dopamine system.

Proposal for Pagoclone Drug Trials

It can take a billion dollars, thousands of patients, and more than a decade to gather evidence to approve a new drug. A big part of the problem with conventional trials is that they essentially take all comers. In some cases researchers might know that some participants may not benefit from the treatment. Those who do not respond can cause a drug to fail even though a significant minority of patients could benefit.


Unless something different is done, we may have to wait a very long time for a fluency improving drug. Perhaps the problem lies in the current policy that it is necessary to absolutely, positively prove (e.g., to the 99.9999% level of certainty) the efficacy of the drug before releasing it to the public. For any potentially fluency improving drug such as pagoclone, we might expect all sorts of objections to be raised when the results of any clinical trials are published. For example, although improvement may have been observed in a clinical setting, will this improvement be observed post-clinically after a long period of time? Is the disfluency counting method reliable? Etc., etc.

The most vociferous critics of fluency drug testing (e.g., The Stuttering Brain blog; Roger Ingham, Journal of Clinical Psychopharmacology, October, 2010) rely heavily on the placebo argument to bolster their beliefs and prejudices--namely that individuals respond favorably to a particular drug not because of its therapeutic efficacy but rather through a placebo effect. And, according to them, this effect might be short lived. Since stuttering is basically a mind-body problem, and the mind plays a very important role in the severity of the disfluency, it is no wonder that it is very difficult to disentangle any real therapeutic effects from placebo effects. In addition, naturally occurring fluctuations in the levels of neurotransmitters may further obfuscate clinical trials. Listening to these critics may result in paralysis through analysis with regard to the search for fluency enhancing drugs.

So my proposal is that for such a drug like pagoclone, why not release the drug on the market AFTER testing for safety? In this way, a population larger than that of any clinical trial could try the drug and decide for themselves as to its efficacy. In essence, it will be the market that decides its success or failure. For some, the drug may prove to be a boon to their fluency, while for others the effect may wear off after time. If the effect does wear off, it does not necessarily imply a placebo effect. An alternative explanation might be that tolerance to the drug may have been built up. In which case, for these people, the drug would better be used in a punctuated fashion with periods of use separated by periods of no use. And, of course, there may be a group for whom the drug does not work at all.

The final concern would be the cost of the drug to the consumer if it were released in this fashion. In the ideal, the cost of a drug that has less than strongly proven efficacy should be less, since the cost of excessive testing was substantially reduced. However, given that the capitalistic system is what it is, perhaps the government should step in and regulate not only the release of such drugs, but also their cost, much as governments often regulate the prices that utilities charge for their products or services.

Beyond Pagoclone, Part 1

Amazingly, for many decades articles published in the medical literature indicated that BZs had no impact on the fluency of stutterers. More recently with the advent of the dopamine hypothesis of stuttering, medical researchers as well as individuals using BZs off-label have reported its positive effects on fluency. And, of course, with the recent testing of pagoclone, which acts much like a BZ in facilitating GABA binding and consequently blocking dopamine activity, the role of the GABAergic system as it affects fluency has come to the fore.


In fact, as was pointed out in a recent post (see "Atypical Antipsychotic Drugs and Stuttering"), it may be a dearth of GABAergic activity in the motor neuron section of the brain that leads to reduced fluency rather than excessive levels of dopamine or an overabundance of dopaminergic receptors. If this were the case, we would then have a GABAergic hypothesis of stuttering.

With this in mind, we look beyond BZs and pagoclone in this post to medications that may affect GABAergic activity by other means. In a previous post entitled "Stuttering, GABA, and Benzodiazepines", we pointed out that GABAergic activity can be enhanced in several ways. First, we can facilitate its uptake to post-synaptic neurons by using, for example BZs or pagoclone. Second, we can increase the amount of GABA or GABA analogues in the synapses. And, thirdly, we can reduce its re-uptake into the pre-synaptic neurons, in effect maintaining higher GABA levels in the synapses. In this post we focus on the last two approaches to affect GABAergic activity.

The classes of drugs we discussed previously fall loosely into the anti-anxiety (e.g., BZs) and the anti-psychotic (e.g., zyprexa) categories. The drugs discussed here fall generally into the anti-epileptic category. The following are just a representative sampling of the scores of drugs in this category.

Vigabatrin increases the level of GABA in the synapses. It does so by inhibiting the action of the enzyme, GABA-transaminase (GABA-T), which is responsible for the elimination of GABA. Moreover, when GABA-T reacts with GABA, it ultimately leads to the production of succinic acid and succinic acid further inhibits the production of GABA. Vigabatrin has been implicated in causing visual field defects, specifically affecting the outer area of the retina.

Depakote has no effect on GABA-T but instead reduces the level of succinic acid itself so that the production of GABA is not inhibited. A potential drawback of Depakote is that it may adversely affect the pancreas.

Phenibut acts as a GABA analogue binding primarily at GABA-B receptors but to some extent at GABA-A receptors. This drug has been widely used in Russia as an anti-anxiety medication, to treat insomnia, as an anticonvulsant, and as a treatment for stuttering. It has been available over-the-counter in the United States. There is some risk of drug dependency and withdrawal symptoms when usage of this drug is discontinued.

Other drugs that act as GABA analogues (also called GABA-mimetics) include Baclofen, Progabide, Fengabine, and Tolgabide.

Gabapentin increases GABA primarily by enhancing the release of GABA from glia, which are non-neuronal cells within the brain. The structure of gabapentin is similar to that of GABA but it does not act directly on GABA receptors. When administered over an extended period, there was no evidence of tolerance or physical dependence after abrupt termination.

Tiagabine, a GABA reuptake inhibitor, blocks the activity of GABA by binding onto GABA receptor sites of presynaptic neurons, which then prevents the reuptake of GABA into these presynaptic neurons. Thus, more GABA will be present in the synapses and available for binding onto post-synaptic neurons.

In summary, since the track record of the medical establishment in identifying drugs that may improve fluency has been extremely poor and research on candidate drugs is moving at a snail's pace, the purpose of this post is to stimulate thinking in this area. The most likely classes of existing drugs that may be possible fluency enhancing candidates are those associated with relieving anxiety, alleviating psychosis, or controlling epilepsy/convulsions.

Grants for Hollins Institute

In the September 21st edition of the Wall Street Journal (the New York section, not available to all readers), an article appeared about Sander Flaum. He is a marketing consultant and adjunct professor at Fordham University. Mr. Flaum stuttered until the age of 30, at which point he enrolled in a speech therapy program at the Hollins Communications Research Institute in Roanoke, Virginia. He claims to have gotten his fluency problem under control, but still needs to practice daily.


Through the Rose Flaum Foundation, he is offering grants of up to $4000 to those in need who wish to enroll in the Hollins program, which is several weeks long. The Foundation is funding the program to the tune of $100,000 per year, so there should be over 25 grants offered each year. No contact information was given in the article.

Atypical Antipsychotic Drugs and Stuttering

Stuttering may be caused by excessive dopaminergic activity in the motor neuron section of the brain. More specifically, it is the dopaminergic activity in the nigrostriatal pathway involved in motor function that has been implicated in stuttering. On the other hand, excessive dopaminergic activity in the mesolimbic pathway involved with emotion and memory has been linked to schizophrenia. Since individuals who stutter generally do not exhibit schizophrenic tendencies, the levels of dopaminergic activity are obviously unique to different parts of the brain.


In several of the previous posts, we indicated that one way to inhibit the activity of dopamine is to enhance GABAergic activity, which can be accomplished with BZs or pagoclone. Although the claim has been made that stuttering is linked to too much dopaminergic activity, the problem may be that there is too little GABAergic activity in the relevant sections of the brain. There are other drugs that may enhance GABAergic activity and we will discuss these in future posts.

But in this post, we want to discuss more direct approaches to limiting dopaminergic activity, namely through a class of drugs called atypical antipsychotics. These drugs, which include Risperidone, Zyprexa and Abilify, were designed to treat conditions such as bipolar disorder, schizophrenia, mania, and delusional disorder. More recently, they have been used off-label to treat stuttering.

These drugs work directly in that they block dopamine receptors (namely the D2 receptors) on neurons so that dopamine that is present in the synapses cannot itself bind to these receptors. In this way, the activity of dopamine is reduced.

This variety of drug therapy has been strongly promoted by Dr. Gerald Maguire, the director of the Kirkup Center for the Medical Treatment of Stuttering at the University of California, Irvine. For those who are interested, the web-site of the Center is:

                            http://www.healthcare.uci.edu/psych/stuttering/

Unfortunately, atypical antipsychotics may have some side effects such as sedation, dyskinesia (involuntary muscle twitching) and may lead to weight gain and potentially diabetes. Major research is currently being conducted to develop a new generation of atypical antipsychotics exhibiting reduced drug side effects.

Pagoclone, GABA, and Stuttering

Pagoclone had previously been tested as a drug to relieve anxiety. One of the participants in the study who stuttered noted that when taking the drug he experienced greater fluency. So it was decided that larger scale trials would be conducted to test the efficacy of pagoclone as an anti-stuttering medication.

Pagoclone is a member of the class of drugs called cyclopyrrolones. However, it acts like a BZ in that it binds to BZ receptor sites on neurons, the difference being that it binds only to some of the subtypes within a BZ binding site, specifically to the alpha-2 and alpha-3 subtypes. Hence, it does not have some of the negative effects of BZs such as causing sleepiness and, it is claimed, less tendency to induce physical dependency, addiction, and tolerance. In any case, pagoclone facilitates the binding of GABA to post-synaptic neurons which in turn inhibits the action of dopamine, implicated in stuttering.

Pagoclone had been in phase 3 drug testing by Endo Pharmaceuticals, but the testing program was abruptly halted recently. No explanation to this date has been given. A number of individuals partaking in the program have anecdotally reported positive results. In most cases disfluency was substantially reduced but not completely eliminated. It would seem that the humane move by Endo would be to test the drug for safety, release it to the public, and let the market determine its fate.

Many individuals who stutter and have not been part of the testing program had been eagerly waiting for pagoclone to reach the market. Many are curious as to whether or not this drug would improve their fluency. Perhaps this question might be answered indirectly by trying a BZ instead. Since the action of the two drugs is basically the same, the extent of fluency improvement using a BZ might give an indication of the potential efficacy of pagoclone for any given individual.

Stuttering, GABA, and Benzodiazepines

In the last post, we discussed the neurochemistry of the brain and its effect on stuttering. In particular, the neurotransmitter GABA acts as an inhibitor and reduces the effect of the neurotransmitter, dopamine, which has been implicated in stuttering.

In this post, we discuss various drugs that may enhance the action of GABA. There are basically three mechanisms to accomplish this:

      • The amount of GABA in the synapse between two neurons may be enhanced
      • The reuptake of GABA into the presynaptic neuron may be inhibited, thus
         maintaining the level of GABA in the synapse
      • The binding of GABA onto the post-synaptic neuron may be encouraged.

Benzodiazepines (BZs) are drugs that encourage the binding of GABA onto post-synaptic reeptors. The mechanism involved is that BZs themselves bind to BZ receptors on the neuron. BZ and GABA receptors exist together in an interactive complex. In effect, the binding of BZ facilitates the binding of whatever GABA is in the synapse (one of the puzzles of neurology is that there are BZ binding sites on neurons but BZ is not a naturally occurring chemical in the brain). And when GABA binds to a neuron, as shown in the diagram of the previous post, it inhibits the action of dopamine in the motor neuron section of the brain, hence improving fluency. Examples of BZ drugs are Valium, Ativan, and Xanax.

While BZs may reduce the incidence of stuttering through the mechanism cited above, they also have side effects such as the reduction of anxiety and sleep inducing properties. While the former may be beneficial for a stutterer since stuttering is partially a mind problem (see the post on the Mind-Body Problem), the later property is a liability. In addition, with continuous use a dependence and tolerance may be built up for the drug. So BZs should be used selectively and sporadically for situations when the individual expects to be in an anxiety producing situation such as speaking before an audience or engaging in a job interview. In such situations, the effect of the BZ should be to improve fluency and not have much of a sleep inducing effect because of the high initial state of anxiety.

Some stutterers using BZs have also reported that it heightens the level of their articulateness. Thoughts, ideas, and words seem to flow more smoothly. This phenomenon may be explained in two ways. First, greater fluency enables one's speech to keep up with one's thoughts, so there is a closer temporal match between thoughts and speech. Secondly, a study conducted in a nursing home indicated that patients given low dosages of a BZ became more lucid in that they were able to communicate in a more coherent manner. The speculation was that administration of the drug reduces "brain noise." So "brain noise" because of excessive dopaminergic activity may be what stutterers have in the motor neuron section of the brain as well as elsewhere in the brain, which may adversely affect articulateness as well as fluency.

In the next post, we will discuss pagoclone and stuttering.

Stuttering and Neurotransmitters

The brain consists of neurons which are basically nerve cells organized to perform specialized functions such as speech. In addition, there are chemicals called neurotransmitters that help to transfer messages in the form of electrical impulses from neuron to neuron.

To understand what happens in the brain when a person stutters as well as how various medications work to reduce stuttering, it is first important to learn about the function of neurons and neurotransmitters.

As shown in the top diagram in the picture at the left, the neuron consists of a cell body, an axon, and numerous branching dendrites at both ends. Messages pass through the brain by traveling through these neuronal structures, beginning as an electrical impulse that is picked up by one of the dendrites of the neuron. Next, the impulse moves through the cell body then travels down the axon. By the time it reaches the end of the axon the electrical impulse is changed to a chemical impulse in the form of a neurotransmitter. These neurotransmitters, released by the axon carry messages from one neuron to another. When the message is picked up by the dendrite of a neighboring neuron, it is changed back to an electrical impulse and the process begins again. Since neurons do not touch each other, the neurotransmitter passes from one neuron to the next through a narrow gap, called a synapse.

Neurotransmitters are specifically shaped so that when they pass from a presynaptic neuron into a synapse, they can chemically bind onto certain sites, called receptors, on a neighboring postsynaptic neuron. Neurotransmitters can fit a number of different receptors, but receptor sites can only receive specific types of neurotransmitters. Upon binding to a receptor site of a neuron, the chemical message of the neurotransmitter may lead to an electrical impulse that continues on its way toward the next neuron, or it may stop where it is. In either case the neurotransmitter releases from the receptor site and floats back into the synapse. It is then removed from the synapse in one of two ways. The neurotransmitter may be broken down by a chemical called monoamine oxidase, or it may be taken back in by the presynaptic neuron that originally released it. This last process is called neurotransmitter reuptake.

The current hypothesis regarding stuttering is that it is caused by excessive dopaminergic activity in the motor neuron section of the brain. The bottom diagram of the picture above shows the detail of a neuronal synapse. The neurotransmitter, dopamine, is released from the dendrite of a presynaptic neuron at the left of the diagram and binds to a dendrite of a postsynaptic neuron (shown as a "tail") in the middle of the diagram.  Dopamine is an excitatory neurotransmitter.  On the right is another dendrite which releases GABA that happens to be an inhibiting neurotransmitter. What this means is that when GABA binds to the postsynaptic neuron, it inhibits or blocks the action of dopamine and hence modulates its excitatory action. So if stuttering is caused by excessive dopaminergic activity, we have several courses of action. The first is to directly block dopaminergic activity in various ways and the second is to increase GABAergic activity by various means.

Dopamine is an agonist, which is a chemical that binds to a receptor of a neuron and triggers a response by that neuron. In addition to dopamine, there are other neurotransmitters in the brain that act as agonists.  Also, drugs introduced exogenously into the brain may act as agonists.  On the other hand, GABA is an antagonist in that it blocks the action of the agonist. And similarly to an agonist, there are other neurotransmitters that are antagonists and drugs may act as antagonists.

In the next post we will discuss drugs that may affect dopaminergic activity in different ways.

Stuttering and Dopamine

The current hypothesis regarding the physiological cause of stuttering is that there is excessive dopaminergic activity in the motor neuron portion of the brain. We emphasize that this is a hypothesis which does not yet have the status of a highly tested theory. Although brain imaging studies have shown that people who stutter exhibit above average motor neuron dopaminergic activity, this observation is a correlation rather than a cause/effect chain. The administration of certain atypical antipsychotic drugs which are known to reduce dopaminergic activity also reduce the level of disfluency and this provides some support for a cause/effect relationship. But additional evidence is needed to further support the hypothesis.

Stuttering begins to manifest itself in preschool children and some children outgrow this fluency problem. Is excessive dopaminergic activity present in the brains of these children? Is there any difference in the dopaminergic activity of children who outgrow their stuttering compared to those who do not? Are there any environmental influences that govern the different paths that children take toward fluency that may influence dopaminergic activity?

In addition, we may inquire as to whether or not any of the psychologically based speech therapies affect dopamine levels. If the effects of these therapies are temporary, can changes in dopamine activity be observed? Also, to what extent does the administration of placebos affect dopamine levels? Do illegal drugs, most of which accentuate dopamine activity, have a negative effect on all or most stutterers?

We also want to get at the question as to what causes the physiological structure of the brain that results in excessive dopaminergic activity. Is it nature or nurture? Are there specific genes that can unambiguously be associated with stuttering? Or does nurture in the way of the environment play a major role in the development of disfluency? If the problem is principally with genes, is some sort of gene therapy possible for the treatment of this problem?

These are some of the questions that need to be answered before the dopamine hypothesis can be accepted as a theory.

Parkinson's Disease, Dopamine, and Stuttering

In the previous blog entry, we discussed the possibility of a nocebo-like effect having an influence on stuttering. Basically, the context in which an individual finds himself can have a negative effect on his fluency. This is a result of a conditioning mechanism whereby a specific context is associated with greater disfluency.

Victims of Parkinson's disease have a deficit of dopamine activity in the same area of the brain in which stutterers have an overabundance. And an interesting observation is that Parkinsonism patients receiving a placebo showed a substantial increase of dopamine activity in this part of the brain according to brain imaging results. So we can wonder if, similarly, the nocebo-like effect of context on stuttering might also increase the level of dopamine activity in the brains of stutterers, thus negatively affecting their fluency.

The diagram discussed in the blog entry entitled "Mind/Body Problem" is repeated here with the specific labels related to stuttering replacing the generalized labels of the previous diagram.  Note that the "Anxiety" label was replaced with the "Mind" label since anxiety can be viewed as a state of the mind.  So basically, stuttering affects the mind (i.e., causes anxiety) which in turn affects stuttering.  In addition, the context (e.g., speaking before an audience), through conditioning, further affects the mind and the subsequent lack of fluency.
However, given the possible dopamine connection discussed above, we can modify the diagram as follows:

 Note that the directed line now goes from "Mind" to "Excessive Dopamine Activity) instead of going to the "Stuttering" node, reflecting the possibility that context, acting as a nocebo, will directly affect dopamine activity which in turn affects fluency. This representation of the mechanism for stuttering has the advantage of following the law of parsimony in explaining stuttering.