Stutter-Mind-Body

Brain Imaging and Stuttering

2012-01-25T18:42:00.002-05:00

An interesting article appeared in the Wall Street Journal (January 24, 2012) entitled “Probing the Brain’s Mysteries.”

Much like mapping the elements of the human genome (i.e. the Human Genome Project), researchers are making great strides in mapping the basic wiring of the brain through what has been called the Human Connectome Project. These studies are expected to illuminate the complex relationships among the billions of neurons responsible for mental functions such as memory, reasoning, emotion and even speech.

The progress has come about through advances making magnetic resonance brain scans 7 times more quickly and the analysis of neural connections 50 times faster than a year ago. In addition, techniques have been developed to better reveal the brain’s connections.

This information for several thousand individuals is being input to databases of brain scans, medical data, psychological profiles, and genetic information. The database, which will be available for others to analyze, may be useful in uncovering ailments, such as stuttering, associated with the malfunctioning of neural connections.

The task at hand is monumental in that the human brain has a million times more connections than the genome has letters of DNA. The automation of the mapping of individual synapses is expected to facilitate this effort.

The Human Connectome Project is a five year effort funded by the National Institutes of Health. The work is done by combining four imaging techniques, including a new method called diffusion magnetic-resonance imaging that allows the mapping of white matter nerve fibers for the first time.

In addition a human brain atlas providing an interactive guide to the brain’s anatomy and genes is near completion at the Allen Institute for Brain Science. The Institute intends to link the brain atlas to data from the Connectome Project.

Researchers in communication disorders such as stuttering should take advantage of this trove of information to help elucidate its neurological underpinnings. I would hope that individuals who stutter might be included among the individuals in the Human Connectome database.

Reasons to Participate in the Curetogether Survey

2011-12-21T00:55:00.003-05:00

If your concern is solely about yourself and what drug or treatment you could partake in that would enhance your fluency, then perhaps you would not find much utility in taking the Curetogether survey. However, I would think that the typical reader of this blog is an individual of curious mind who might be interested in learning what is behind his/her fluency problem. Hopefully, then, your curiosity is such that you will find useful information derived from the collection of large scale data on a variety of stuttering treatments.

There is virtually no knowledge from large scale studies (i.e., involving a large number of participants) simultaneously evaluating the impact on stuttering across pharmaceuticals, fluency devices, and various speech therapy approaches. And many of the individual studies on specific treatments tend to be self-serving. This is your chance to contribute to one such large scale study. We expect that many Curetogether survey participants likely would have experienced more than one treatment.

The anonymous data that is collected will be available to all. There will be no pharmaceutical company intervention to limit data dissemination in order to protect its proprietary interests. Nor will there be ONLY the availability of aggregated data as is typical of most academic research studies. Data sets at the micro-level will be available to anyone desiring to conduct analyses.

The survey instrument is organic in the sense that it grows as survey participants add items onto the lists of the four survey areas: symptoms, treatments, side effects, and causes. The instrument is by no means perfect since it is a “one size fits all” approach for a large number of medical conditions. The scales used may not be the optimal ones specifically for the collection of data on stuttering. In addition the survey instrument may not get at the combined effect of multiple therapies applied at the same time (e.g., pharmaceutical with speech therapy).

Nevertheless, useful information can be derived from such a large scale data collection. For example, we will get a better picture of what effect pagoclone has had on participants in the drug trials from the participant’s point of view*.

We can also get an estimate of the percentages of individuals in at least two main subgroups (dopamine excessive vs. dopamine deficient) potentially based on survey results involving dopaminergic enhancing drugs (amphetamines) vs. dopaminergic diminishing drugs (atypical antipsychotics, BZs, pagoclone)**.

So please participate in the Curetogether survey at curetogether.com and contribute to the collective good.

Best wishes for the holidays.

__________________________________

* I recognize that some may regard the self-reporting of individuals to be unreliable or any sort of effectiveness perceived by an individual to be the result of a placebo effect. At least one popular pharmacophobic blog devoted to stuttering appears to be overeager to discount an individual’s view and to attribute any positive self-reporting results to the placebo effect.

** Third and fourth subgroups may involve those responsive to both dopaminergic enhancing and diminishing drugs on one hand, and those responsive to neither on the other hand. Such findings would be interesting in their own right.

Curetogether Adds Stuttering

2011-12-13T18:24:00.002-05:00

I suggested that the Curetogether organization might add stuttering to its list of health conditions. The response from Daniel Reda, one of the co-founders of Curetogether, is as follows:

We've just added Stuttering to CureTogether. Please feel free to add symptoms or treatments that are not already listed. The survey is here -
http://curetogether.com/stuttering/survey/symptoms/

The survey allows you to enter data regarding symptoms, treatments, side effects, and causes.

This is an opportunity to collect some data on stuttering all in one place rather than having anecdotal information scattered throughout the blogosphere. Please partake in this project and express your experiences with various treatments, either positive or negative. If enough data is collected, various statistical analyses can be conducted to shed some light on this fluency condition.

Citizen Involvement in Stuttering Research?

2011-12-12T22:41:00.003-05:00

With the dashing of hopes that pagoclone might eventually be released to the market, the slow pace of medical research for palliatives/cures for stuttering, and the reluctance of researchers and pharmaceutical companies to release data, we propose an alternative path. This path is suggested by an article in the Wall Street Journal (December 3, 2011) entitled “Citizen Scientists.”

As the article headline claims, “ordinary people are taking control of their health data, making their DNA public and running their own experiments”. An organization called Genetic Alliance is part of a growing movement that empowers patients to control and analyze their health data in order to advance medical knowledge. The on-line posting of personal medical information and its public availability is the key to such initiatives.

The citizen scientists involved in these efforts may use the internet to run experiments and clinical trials as well as perform their own analyses. The experiments generally test drugs, approaches or devices that are already available as opposed to some new, for example, drug. And the results of some of these experiments are being published by medical journals.

An on-line site dedicated to patient-driven research concerning the efficacy of treatments for a variety of health conditions (close to 600 at this date) is Curetogether.com. This website collects data from individuals through survey instruments regarding their symptoms, treatments, side-effects, and causes.

The results are tabulated and presented in graphical form. Participating individuals may add further observations through a “Post Your Comment” discussion section. In addition, the data are presented in cross-tabulation form with effectiveness along the y- axis and popularity (extent of use) along the x-axis.

The Curetogether organization encourages partnerships with research organizations, universities, and self-experimenters. It collaborates on and sponsors a number of research studies using the collected data.

Unfortunately, among the health conditions covered, stuttering is not included. Clearly, its inclusion would be of benefit to those individuals who are disfluent in terms of identifying treatments that may be of use as well as avoiding those that are ineffective and perhaps costly. The data might also provide insights that could improve the understanding of stuttering and lead to future advances.

Critics may claim that data gathered through citizen involvement might not be collected in a rigorous fashion, that conclusions may be drawn from sample sizes too small to yield statistically valid results, or that self-selectivity biases may undermine the conclusions. While in some cases this may be true, the data collected and the resulting studies nevertheless are useful in pointing the way to future research efforts either by citizen scientists or professionals.

Breaking News About Pagoclone

2011-12-02T00:15:00.000-05:00

I have received the following comment from Dr. Gerald Maguire, UC Irvine School of Medicine, who has been involved in the pagoclone trials:

Thank you for your informative blog. I would like your readers to know that Endo Pharmaceuticals has decided to focus on their core business of urology and pain management and will not continue the pagoclone stuttering research program. Our university will be starting our next pharmaceutical trial of asenapine in stuttering in the coming weeks. We are fortunate that Merck has funded this important double-blind trial in stuttering. The mechanism of asenapine, being a dopamine-antagonist, is more clearly defined in stuttering than the partial dopamine agonist of pagoclone. Keep up the great work with your blog!

We will be looking forward to the publication of the results from the pagoclone stage 2 trials by Dr. Maguire et al.

False Negative Impacts on Drug Trial Outcomes

2011-11-23T23:01:00.003-05:00

In the pharmacological research literature, much has been made about the placebo effect and its impact on drug effectiveness measures. Individuals who might be highly suggestible may respond positively to a drug even though it may have no appreciable biological effect on them. Thus, a drug trial that did not take this effect into account could report effectiveness results that are biased upward because of these false positives.

On the other hand, little attention has been devoted to the adverse impact that false negatives can have on drug effectiveness measures. Some trial participants may be treatment resistant, and even though a drug might have biological benefits, various psychosocial factors prevent these benefits from showing up.

There are complex relationships among the trial participant, the malady, the medication, and the treatment provider. For some trial participants, factors such as conflicts, defense mechanisms, resistance, and transference at the subconscious level may contribute to false negatives. These psychodynamic factors can be deeply at odds with positive therapeutic outcomes and should be taken into account in any drug trials.

A large NIMH-funded study has shown a medication/treatment-provider effect*. The most effective providers who administered an active antidepressant had the best outcomes, but the most effective one-third of providers had better outcomes with placebos than the least effective one-third of providers administering the active drug.

This study strongly suggests that the relationship between treatment provider and trial participant can play an important role in drug trial outcomes. A trial participant’s positive transference to the treatment provider can mobilize self-healing capacities (i.e., placebo effect) while a negative transference may lead to a nocebo effect.

Furthermore, participants, who are not manifestly resistant to symptom reduction, may nevertheless be motivated to resist virtually any treatment provider on the basis of a transference experience whereby the provider is regarded as untrustworthy or in some way dangerous. Such participants might surreptitiously not adhere to the trial protocol so as not to feel under the control of what they perceive to be a “malevolent” provider.

Then there are trial participants, psychologically resistant to medications themselves, who may have conscious or subconscious factors that interfere with the medication’s effect. Resistance can once again take the form of drug trial protocol non-adherence but also includes participants who are nocebo responders experiencing adverse responses to a medication.

A trial participant’s desire to change is an important determinant of outcomes. Even for participants who enter a trial ostensibly to be helped, some may be conflicted about improving if their malady has created some conscious or subconscious benefits**. Trial participants perceiving significant benefits for their symptoms may, consequently, be reluctant to relinquish these symptoms. Symptoms, in these cases, may thus be an important defense mechanism inhibiting positive outcomes.

For example, a study*** showed that patients receiving a benzodiazepine for anxiety, who were highly motivated to change had the most robust response to the drug, while placebo recipients who were highly motivated had a greater reduction in anxiety than patients taking the active drug who were less ready for change.

The observations above have implications for pharmacological research applied to stuttering. While the root cause of stuttering is some neurological malfunction of the brain, nevertheless various psychological factors eventually come into play. And these factors may interact with a treatment protocol affecting trial outcomes.

In a following post, we will discuss a framework for the correction of false negatives in pharmacological trials.

_______________________________________________

* McKay KM, Imel ZE, Wampold BE. Psychiatrist effects in the psychopharmacological treatment of depression. J Affect Disord. 2006;92:287-290.

** See an interesting blog post in this regard:

http://thestutteringbrain.blogspot.com/2007/10/who-says-stuttering-has-no-benefit.html

*** Beitman BD, Beck NC, Deuser WE, et al. Patient Stage of Change predicts outcome in a panic disorder medication trial. Anxiety. 1994;1:64-69.

Copyright 2011

Stuttering and Gene Therapies

2011-11-13T23:08:00.002-05:00

Stem cell therapies are generally oriented toward the remediation of some chemical deficiency in a living organism. For example, Parkinson’s victims are deficient with regard to the production of dopamine and Type 1 diabetics lack a capability for producing insulin.

The hope of stem cell therapy is that stem cells can be used to make cells producing the vital chemical that is lacking. These cells can then be injected into the relevant organs and, as they took hold, the symptoms of the disease would disappear (hopefully permanently).

A recent study in the journal Nature (November 6, 2011), describes research in which stem cells derived from human embryos were used to treat Parkinson’s disease in rodents. Previous approaches had failed because human derived dopamine cells did not perform efficiently when transplanted into animals; in addition, the transplantations triggered the growth of unwanted tumor-like structures.

In these past experiments, two specialized proteins, known as growth factors, were added to turn embryonic stem cells into dopamine-producing nerve cells. But the recent Nature study added a third substance that activated a crucial biological pathway in the embryonic cells, leading to human dopamine cells that functioned more effectively and that did not lead to tumor-like structures.

What does this study have to do with stuttering? In many cases, stuttering is a result of excessive dopaminergic activity in parts of the brain dealing with speech and its timing rather than some neurochemical deficiency. So, at first glance, it may appear that stem cell therapies might not be relevant.

However, an insufficiency of GABAergic activity in these areas of the brain may be a contributing factor leading to the dopaminergic overactivity (see the blog post entitled “Stuttering and Neurotransmitters,“ August 25, 2010). So if stem cells could be coaxed into generating GABA-producing cells, then, in principal a gene therapy approach to stuttering might be feasible.

The problems with gene therapies applied to stuttering are that there are essentially no animal models with which to test these therapies (perhaps the “stuttering mice?”) and that such intrusive treatments may not be deemed warranted for a “mild” malady such as stuttering. At any rate, we should expect a relatively long time horizon before any such treatments become available. And when they do, we might expect them to be a byproduct of therapies for the treatment of conditions such as schizophrenia.

Downregulation and Stuttering Treatments

2011-10-29T11:58:00.003-04:00

A neural circuit may become desensitized to a drug through a process called downregulation. For example, benzodiazepines (BZs) bind to BZ receptors in the brain which are co-located with GABA-A receptors. BZ binding facilitates the binding of the GABA neurotransmitter to GABA-A receptors. Unfortunately, long term systematic use of BZs generally lead to neuro-adaptations resulting in the reduced binding of GABA (i.e., downregulation).

Similarly, dopamine receptors are typically stable, but sharp and prolonged increases in dopamine levels via stimulants can downregulate (i.e., reduce the numbers of) active dopamine receptors*. As a result of downregulation, drug tolerance increases and dosage escalation is necessary for the drug to maintain its effect.

A kind of downregulation may also be at play with various treatments aimed at alleviating stuttering. A stutterer might experience substantial gains in fluency during the early stages of a treatment but subsequently may regress into disfluent speech. For example, it is commonly reported by users of various delayed auditory feedback (DAF) devices, such as SpeechEasy, that these devices lose their effectivenesses with continued use.

It is not clear that such phenomena can be explained merely as a placebo effect or by the withdrawl of the moral support given by a therapist during the early stages of a treatment. Nor can these regressions into disfluency be explained by a subject’s possible lack of adherence to some strict protocol specified by the treatment. Instead, this diminishing effect over time, in some instances, might be due to an acclimatization or downregulation in the neural circuitry associated with a treatment.

DAF devices work by means of emulating choral speech, which has been recognized as a fluency inducing condition. One theoretical explanation of the effect of choral speech on fluency** is that the loop normally involved in spontaneous speech involving the basal ganglia (i.e., the medial premotor system) is preempted in favor of a downstream loop involving the cerebellum (i.e., the lateral premotor system; see blog post entitled “Stuttering and the Dual Premotor System”).

So it is puzzling as to why the impact of DAFs on fluency fade with time. Some sort of adaptation effects may come into play, but whether or not these adaptations involve neural circuitry downregulation is an open question. At any rate, the research literature is curiously absent of explanations concerning the fleeting effectivenesses of a variety of treatments for stuttering.

________________________________________________

* It is interesting to speculate that the downregulation of dopamine receptors through the excessive use of amphetamines may lead to greater fluency in dopamine-sensitive stutterers by virtue of the fact that dopamine receptors are downregulated. However, this effect might only be temporary.

** Other explanations of the impact of DAFs on fluency revolve around impaired

auditory feedback and its impact on fluency.

Is Stuttering Disruptive?

2011-10-11T17:28:00.000-04:00

An interesting article appeared in the NY Times regarding a student who stuttered and was shunned by his teacher during classroom discussions. See:

http://www.nytimes.com/2011/10/11/education/11stutter.html?ref=todayspaper

The article also contains some useful information regarding an acting/playwriting group in NY for stutterers.

Time Elasticity, Stuttering, and Pagoclone Trials

2011-09-27T12:01:00.002-04:00

Researchers at UCLA conducted an experiment regarding the estimation of time intervals. Subjects, some of whom were on stimulants, were asked to give their subjective estimates of the time elapsed between a start signal and an end signal. The actual length of the interval was 53 seconds. The average time estimates of the non-stimulant group was 67 seconds, while that of the stimulant group was 91 seconds.

Stimulants increase the dopaminergic activity in the brain. The perception of time-intervals is thought to be mediated by spiny neurons in the striatum of the basal ganglia, whereby timing initiates with a burst of dopamine and ends with a recognized signal.

Naturally occurring variations of dopamine levels in the striatum may affect fluency levels for a subgroup of stutterers. So the relevance of this study is that these individuals may find that they have an expanded subjective experience of time much like the stimulant group in the experiment. And this time elasticity may vary during periods of lesser or greater fluency as dopaminergic activity is at different levels.

On the other hand, the subgroup of stutterers whose fluency may be governed by a deficiency of dopamine may find that their subjective experience of time is contracted. In the experiment above they might underestimate the time interval.

An interesting experiment for individuals would be the following: Upon awaking in the morning, look at the clock. Remain in bed for a few minutes, estimate how much time you think has elapsed, and then compare it with the clock time. Calculate the ratio of estimated time to clock time and record it. During the day, observe your level of fluency (in particular, as close to waking time as possible). For example rate it on a 1 to 10 scale. After several months, compare the time interval ratios to your fluency levels (i.e., by eyeballing or more rigorously by a correlational analysis) in order to determine if there is an association between the two measures.

IF the time interval ratio is a plausible proxy for dopamine levels and IF stuttering is affected by dopamine levels, then you should get a reasonable correlation between the two measures. We would expect the correlation to be positive for the subgroup disfluent for high levels of dopamine and negative for the subgroup disfluent as a result of low levels.

In previous posts, we suggested that stutterers involved in clinical drug trials be screened on the basis of their subgroup membership. There is no reason to dilute the clinical trials group, for example in pagoclone studies, with individuals whose fluency is not affected by high dopamine levels. In particular, we suggested that the response of their fluencies to a benzodiapine might be a criterion for identifying subgroups.

But governmental drug administration agencies (such as the FDA) may disapprove of the selection of individuals for drug trials based on their responses to another drug. So the use of time elasticity measures as discussed above might qualify as an alternative selection mechanism.

Limbic Stuttering

2011-09-08T19:56:00.002-04:00

We have previously discussed the possibility that stuttering may have two components: one generated by brain disfunctions and the other generated by the “mind.” The mind is a manifestation of the brain and involves, in particular, emotions. Hence, we now refer to stuttering generated by the mind as limbic stuttering, since the limbic system is instrumental in determining emotions.

Limbic stuttering may be engendered, for example, by a specific social context (e.g., speaking before an audience) or by an anticipatory emotional reaction when coming upon a word having a sound over which one has previously blocked (e.g., any words starting with “f” such as “favorite”).

As discussed previously, some theories of stuttering posit that the disruption of timing signals between the basal ganglia and speech motor areas in the left cortical hemisphere contributes to or causes stuttering. The dorsal striatum in the basal ganglia is involved in the timing of speech and excessive dopaminergic activity in the dorsal striatum disrupts timing signals for a subgroup of stutterers.

The ventral striatum, in physical proximity to the dorsal striatum, is part of the limbic circuitry governing emotions. Emotional activation of the ventral striatum (e.g., coming upon a feared word) further contributes to the dopaminergic activity that disrupts timing.

Is there any way that we could empirically determine if a blocking incident is limbic stuttering? To answer this question, consider a technique for preempting a block. Namely, when you come to a block, don’t try to plow through it. Rather, stop, go back several words and continue with your sentence. So you might be trying to say, “Let me tell you about my favorite restaurant in New York,” and you perceive a block on the word “favorite.”

Then the approach might be to say, “Let me tell you about my (block) tell you about my favorite restaurant in New York.” Chances are that if the block was not limbic-based, you will be able to complete your sentence without a block. I say “chances are,” since there is a probability that a brain-based block (as opposed to mind) may again repeat itself on the word “favorite.”

Note that this approach of repeating several words is related to voluntary stuttering on a syllable such as “f-f-f-favorite,” and might be characterized as voluntary phrase stuttering. If block occurrences in one’s speech are not excessively frequent, then this approach may not be viewed as disfluency from the listener’s point of view.

However, it is unlikely that the technique will be effective for limbic stuttering since anticipatory fear will repeatedly activate the dopaminergic system. Thus, the technique’s lack of efficacy might be regarded as an indicator of limbic stuttering.

The Cerebral Cortex and Stuttering, Part 2

2011-08-31T09:44:00.001-04:00

Per Alm has recently published a chapter in a book focusing on cluttering. As he points out, since stuttering and cluttering are overlapping but contrasting disorders, understanding cluttering may help in understanding stuttering. A lot of the presentation below, representing a theoretical framework for the production of speech, owes much to this chapter. However, I take full credit for any misrepresentations that I may have made.

In this post, we focus on the medial cortical areas that are involved in the production of speech. Specifically, these are the motor cortical areas, which are typically divided into three regions having different functional roles:

• pre-motor area (PMA)
• supplementary motor area
• primary motor cortex(M1)

The premotor cortex guides movements of the vocal apparatus by integrating sensory information. It helps to regulate motion by dictating an optimal position to the motor cortex for any given movement.

The supplementary motor area lies just in front of the primary motor cortex. What had previously been regarded as the supplementary motor area is actually composed of two anatomically and functionally distinct parts: the supplementary motor area proper (called the SMA) and the pre-SMA (see figure*).

The Pre-SMA and the PMA function in processes that are preparatory to speech. The pre-SMA is involved in acquiring new motor sequences, being more active when the sequence is novel as opposed to one that had already been learned. Higher level planning and sequencing takes place in the anterior pre-SMA, while the posterior pre-SMA is involved in the sequencing of sounds and syllables.

The SMA, along with M1, functions in the initiation and execution of movement. The SMA is responsible for the coordination of sequences of motor movements such as those involved in speech. It is concerned with actions under internal control, for example the retrieval of a motor sequence from memory involving the pronunciation of a word.

SMA neurons are more active when the task requires the arrangement of multiple movements in the correct sequence and correct temporal order. Specifically, the timing of an articulation and the speech rate is controlled by the SMA with support from both the basal ganglia and the cerebellum. And it is this timing mechanism that has been implicated in stuttering.

The purpose of the primary motor cortex (M1) is to connect the brain to the lower motor neurons via the spinal cord.

Aside from the motor cortical areas mentioned above, the anterior cingulate cortex (ACC)** plays the role of a central executive in the production of speech The ACC (as well as the preSMA) are involved in assembling the phrase, from the selection of words and word forms to the sequencing of the words.

In addition, the ACC is involved in the high-level monitoring of speech errors (along with the SMA) through auditory connections. There seems to be a lack of such monitoring among clutterers who seem to be unaware of their disfluency as pointed out in Per Alm’s chapter.

Stutterers, on the other hand, may not have this problem. Instead they seem to be able to monitor their speech errors and are aware of their disfluency to such an extent that they ultimately regress into secondary stutttering patterns such blocking, etc. However for stutterers, the auditory aspects, feedback, and timing associated with this monitoring may be deficient as shown in a number brain imaging studies.

The ACC, the pre-SMA, and the SMA represent an assembly center for spontaneous speech that retrieves the linguistic components from the left lateral cortex regions such as Broaca’s and Wernicke’s areas. And as discussed in a previous post, the selection of a single word from a number of competing alternatives is further facilitated by the basal ganglia through a winner-take-all function.

Brain imaging studies have shown that stutterers exhibit deficiencies in the left cortical areas discussed above, while the right hemisphere tends to be overactive. However, the greater right hemisphere activity may merely reflect a compensatory mechanism due to the left hemisphere deficiencies. Similarly, it is unclear at this point as to whether: (1) the activity level deficits in these left cortical regions are a secondary effect of dysregulation of the basal ganglia circuits, (2) the left cortical activity level deficits cause dysregulation of the basal ganglia, or (3) deficiencies in both these areas of the brain simultaneously contribute to disfluency.

______________________________________
* This figure, taken from Per Alm’s chapter, represents the medial portion of the brain’s left hemisphere, i.e., split in half from front to back; the figure in the Part 1 post represents the exterior of the left hemisphere of the brain.

** More specifically, that part of the ACC identified as the cognitive ACC.

The Cerebral Cortex and Stuttering, Part 1

2011-08-15T17:27:00.000-04:00

We have thus far focused heavily on the basal ganglia as a potential root cause of stuttering. In the next two posts, we discuss the possible role of structures in the cerebral cortex involving speech processes that may either be affected by or directly contribute to disfluency.

The functional location of speech is principally in the left hemisphere of the cerebral cortex for the great majority of right-handed people. For left-handed people, the picture is less clear; some show a specialization for speech in the left hemisphere, while others specialize in the right, and for still others, both hemispheres contribute just about equally. In the following we focus on the vast majority of individuals who specialize chiefly in the left hemisphere.

A number of brain imaging studies have shown that stutterers exhibit a deficient involvement of the left cortical hemisphere in speech activities and greater involvement of the right. An excess of testosterone in newborns due to stress at the time of birth might well be one of the most common causes of slower development in the left hemisphere resulting in greater participation by the right.

Located in the left lateral cortex regions, as shown in the figure below, Wernicke’s and Broca’s areas are involved in the initiation of speech.

There are three sub-areas within Wernicke’s area. The first responds to spoken words (including the individual’s own); the second responds only to words spoken by someone else (but is also activated when the individual recalls a list of words); and the third is associated with producing speech. Basically Wernicke’s area relates to the representation of phonetic sequences, regardless of whether the individual hears them, generates them himself, or recalls them from memory.

Broca’s area is another part of the complex network involved in developing an articulation plan. It is concerned with the meanings of words (i.e., semantics), how words are combined to form phrases and sentences (i.e., syntax), and the specific sounds associated with words (i.e., phonology).

Broca's area is associated with the serialization of coordinated action of the speech organs.

Various injuries or deficiencies in Broca’s and Wernicke’s areas lead to aphasia which is the partial or total loss of the ability to articulate thoughts and ideas. For example, injuries to Broca’s area may result in agrammatism which typically involves a lack of use of syntax in speech production resulting in laboured speech. Individuals with Wernicke's aphasia have difficulty recalling correct words for the context or they may coin meaningless words.

Being articulate (as opposed to fluent)* depends upon the rich complex of information generated in lateral areas of the cortex, namely Wernicke’s and Broca’s areas. This information is then transferred to medial cortical areas adjacent to Broca’s area such as the motor cortex, which governs the mechanics of speaking. Current theories of stuttering do not implicate the lateral areas as root causes of disfluency. However, stuttering may affect being articulate by virtue of the interruptions of one’s train of thought and the fact that excessive energy and effort is devoted to the mechanics of speaking, which takes away from the focus on content (i.e., what you say).

In addition to the left lateral areas of the cortex, the right hemisphere also comes into play for speech. Prosody refers to the intonation and stress with which the basic units of a language (called phonemes) are pronounced. Feeling and attitude are conveyed through prosody as well as the melody, inflection, and intonation of one's voice and by varying the pitch, inflection, timbre, stress contours, and the rate/amplitude of speech. These aspects of speech enable a speaker to convey and a listener to determine intent, attitude, feeling and meaning. These capacities, both for the speaker (governing the style of presentation, i.e., how you say it) and the listener (interpreting the style), are predominantly mediated by the right half of the cerebral cortex.

Once again the effort/energy spent on stuttering, attempting to speak fluently, or using fluency shaping techniques impairs the ability to convey emotion through one’s speech. As a result, stutterers may speak and behave in a way that seems flat and emotionless.

In the next post, various aspects of the medial cortical areas as relates to speech will be discussed.

*************************************************
* While the aphasias discussed above are regarded by the medical establishment as fluency problems, I prefer to distinguish between being fluent and being articulate.

Subgroups and Drug Testing Trials

2011-08-04T23:50:00.001-04:00

The existence of subgroups among stutterers may lead to the appearance of reduced efficacies for any therapeutic treatment under test. For example, some stutterers may respond to dopamine blockers such as atypical antipsychotic drugs while others may respond to dopamine agonists such as amphetamines. Including both of these subgroups within a drug testing trial will lead to reported results that are less robust.

In other areas of medical research, attempts have been made to identify individuals for inclusion in drug trials based on some measurable characteristic. For example, researchers have identified certain genetic traits among breast cancer victims on the basis of which these individuals may have a greater chance of success in the trials.

With regard to stuttering, the level of knowledge has not yet reached the stage whereby subgroups can be identified on the basis of genetic analyses. However, there may be other means for identifying subgroups.

For example, in selecting individuals for a trial of a dopamine antagonist such as an atypical antipsychotic, a pretrial might be conducted to choose individuals on the basis of their responses to a benzodiazepine (BZ). BZs effectively block dopamine by indirect means, so that an individual whose fluency improves on a BZ might be in the same subgroup responsive to an atypical antipsychotic. The effect of the BZ on fluency should be apparent within half an hour after administration. On the other hand, an individual whose fluency either deteriorates on BZs or remains the same might be in the amphetamine responsive group (or in a potentially third subgroup responsive to neither treatment protocol).

We can additionally refine this selection approach by further screening for individuals who may be particularly responsive to placebos. During the pretrial, a subject might be given a BZ on one day and a placebo on another. An individual who responds positively to both the BZ and the placebo would be eliminated as a trial subject.

The approach outlined above is by no means perfect. BZs affect the limbic system (involving emotions) more strongly than atypical antipsychotics. Since the limbic system (via the ventral striatum) may affect fluency (see the “An Anxious Mind Affects Stuttering” posts), the drug trial group chosen by the above approach may still contain individuals (i.e., false positives) who are not responsive to dopamine antagonists.

The pretrial/trial approach may give a more accurate measure of the effect of a drug on a particular subgroup.

The Direct Pathway and Winner Take All

2011-07-22T23:17:00.000-04:00

The direct pathway conveys motor signals governing speech from regions within the cerebral cortex through the basal ganglia. The basal ganglia is responsible for choosing from among competing motor signals the one that best conveys the intent of the speaker. This process may involve, for example, the selection of a single word from among a number of competing alternatives.

The manner in which this selection is facilitated by the basal ganglia circuits is through a ‘winner-take-all’ mechanism. And this is where the indirect pathway comes into play. As indicated in the previous post, the indirect pathway provides inhibitory signals that effectively screen out the unwanted motor signals.

A more complete representation (than the one presented in the previous post) of the signals from the direct pathway is shown in the figure below. The “preferred” speech motor signals are the first, fourth, fifth, and ninth signals in the diagram. The remaining competing signals are less preferred and have substantially smaller amplitudes.

If the amplitudes of the inhibiting signals from the indirect pathway are at level A, then the less preferred competing signals will be screened out. There then may be a sufficient amplitude of the preferred direct pathway signals above the inhibiting “noise” of the indirect path to execute the speech motor function. On the other hand, if the inhibiting signal amplitudes are at point B, some of the preferred signal amplitudes may be too weak to execute the associated motor functions.

We indicated in the previous post that possible areas of brain dysfunction leading to disfluency may reside in the midbrain, namely various components of the basal ganglia, or in the cerebral cortex itself. Weak signals emanating from the cortex or the inability of the basal ganglia to process adequate incoming signals may result in disfluency.

We can liken the basal ganglia to a radio receiver and the cerebral cortex to a radio station. A particular radio station may be sending weak signals and the gain* of the receiver’s amplifier may not be adequate to increase the amplitude of this signal. On the other hand, the signal from the radio station may be adequate, but the amplifier may be faulty in that it generates a lot of static noise that effectively blocks the signal.

___________________________________________________

* The gain of an amplifier is the ratio of output amplitude to input amplitude

Subgroups of Stutterers

2011-07-09T15:42:00.000-04:00

Some stutterers are responsive to dopamine D2 receptor antagonists such as atypical antipsychotic drugs. Others may be responsive to psycho-stimulants such as amphetamines. According to our current theoretical understanding, these subgroups have in common a neurological dysfunction, specifically in the cortical-basal ganglia-cerebellum complex.

In a previous post, “Direct/Indirect Pathways and Fluency,” we saw that excessive D2 receptor density in the putamen may lead to stuttering. On the other hand, if, for example, the density of D1 receptors in the putamen is deficient, then speech motor signals through the putamen, the globus pallidus interior, and thalamus (i.e., along the direct path) may be attenuated. Or, alternatively, weak speech motor signals may emanate from the sensorimotor cortex areas responsible for speech to the putamen.

The indirect pathway provides a diffuse background of nerve impulse inhibition, which suppresses potentially conflicting and unwanted motor patterns. If the speech motor signals along the direct pathway are weak, then a “normal” level of this inhibitory background will overwhelm these signals.

Given this theoretical picture, we can elaborate on the signal/noise graphs first discussed in the post, “Stuttering and the Medial Premotor System.” The speech motor pattern signals along the direct pathway for fluent individuals are shown in Figure 1, while the diffuse background of nerve impulse inhibition is depicted in Figure 2. Figure 3 shows the combination of the direct and indirect path signals. Note that the direct pathway signals rise substantially above the diffuse background of the indirect path. In other words, the signal to noise ratio is high.

The comparable diagrams are shown in Figures 4, 5, and 6 for the amphetamine responsive subgroup. For this subgroup, the direct pathway signals are attenuated and barely peek above the diffuse backround inhibition. If either a D1 receptor density deficiency or a weak cortical signal is the problem, then psycho-stimulants such as Ritalin or Adderal among the legal drugs, and cocaine and various other “street” psycho-stimulants among the illegal enhance the direct pathway signaling. Psycho-stimulants have been shown in animal experiments to depend for their effect on their action on D1 receptors.

On the other hand, for the subgroup responsive to atypical antipsychotic drugs, Figures 7, 8, and 9 depict the signaling of the pathways. For this subgroup, the diffuse background inhibition from the indirect path overwhelms the direct pathway signals. Since the direct pathway is modulated by dopamine D2 receptors, atypical antipsychotic drugs being D2 receptor antagonists act to reduce the level of this background inhibition.

Aside from the two subgroups discussed above, we can speculate on the existence of a third subgroup--one that has weak direct pathway signaling and strong indirect pathway inhibition. If there were such a subgroup, an interesting drug, LEK-8829*, possessing dopamine D1 agonistic and dopamine D2 antagonistic properties in both the nigrostriatal and mesocorticolimbic dopaminergic pathways, may be of use. Presumably, the drug would enhance the signaling from the direct path while lowering the inhibition of the indirect path.

******************************************************

* Marko Zivin, Potential Applications of Dopamine D1 Agonist and D2 Antagonist LEK-8829, Brain Research Laboratory, , Institute of Pathophysiology, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia E-mail: zivin@mf.uni-lj.si

Published in Slov Vet Res 2010; 47 (4): 175-80

Per Alm's Comments on Blog

2011-07-01T17:22:00.000-04:00

Per Alm sent this stimulating commentary regarding this blog:

Thanks for a very good and well written blog. It seems like you are doing a thorough work, and that your are an independent thinker -- the anonymous format may make it easier to be strait about what you think. A blog like this can play an important role in the striving for a better understanding of stuttering.

Regarding this posting I just have a comment about a detail: "Parkinson’s disease victims, like stutterers suffer from deficiencies with their dopaminergic systems. But their problem is too little dopaminergic activity rather than too much as in the case of stutterers."

I think it is not likely that stuttering persons in general have too high dopaminergic activity. My guess, based on available data, is that anomalies in the dopamine system may be an important factor in some cases of stuttering, but that it is not a core factor in the majority of cases. (For one thing, dopaminergic hyperactivity could be expected to have more widespread effects on personality and other functions. The majority of persons who stutter do not differ from the general population when it comes to personality/temperament, though a subgroup seems to show mild traits of ADHD/ADD.) Further, it is also possible that some cases of stuttering rather is linked to hypo- than hyperactivity of the dopamine system. For example, there are some reports of improved stuttering from dopaminergic stimulants (see summary in Alm 2004, review on basal ganglia, Journal of Communication Disorders).

Another important point is that a partial improvement of stuttering symptoms when using D2 blockers does not necessarily imply that the dopamine system in this person is deviant. D2 blockers reduce the general activity in some brain circuits, which in some cases may improve the overt symptoms of stuttering even if the basic cause is not related to dopamine.

The reason I write this is not that I'm negative towards this type of ideas or towards pharmaceutical trials on stuttering (I'm not), but because there is a risk that a single possible factor gets too much focus and that the great heterogeneity in the stuttering population may be overlooked.

Another thing I would like to comment is that it would be good with more references in the blog. Firstly, because it makes it possible for the interested reader to go to the sources and thereby be able to evaluate the information. Secondly, when no references are given the reader will not know what are "established facts", what are your own proposals, and what are hypotheses put forward by other researchers.

Anyway, again, thanks for your blog!

Per Alm
************

Thanks to Per Alm both for his comments here as well as his writings which have inspired and informed many of the posts in this blog. He has anticipated some of the topics I intended to address in future posts as well as offering some stimulating thinking regarding new directions for this blog.

A comment under the post "Direct/Indirect Pathways and Fluency" by an individual suggests that there are subgroups who are impervious to D2 blocker treatments. So a future post will address this issue.

The possible existence of subgroups may dilute the results of any tests for the efficacy of drug treatments and I'm currently thinking of an approach to drug testing to reduce this dilution.

There is some empirical evidence that parts of the brain outside the basal ganglia may have an impact on fluency, and this issue will be addressed in a future post.

I chose to eliminate references in the posts to avoid their becoming too ponderous. My objective was to restrict posts to within one typewritten 8-1/2 by 11 inch page (this post excluded) for reasons that I will explicate in a subsequent post. The intent is to provide a single post in the future that will contain many of the references that I used ranging from website entries to medical journal articles and texts.

Early Childhood Stuttering

2011-06-29T11:48:00.002-04:00

In the previous post, we showed that stuttering may occur if there is an imbalance between the number of D2 dopamine receptors on the indirect pathway relative to the D1 receptors on the direct pathway. The D2 receptors act as a brake while the D1 receptors play the role of the gas pedal.

In children, stuttering often occurs between the ages of 3-5, many of whom recover spontaneously by age 5, while others persist through the rest of childhood, adolescence, and adulthood. What distinguishes transient childhood stuttering from stuttering that persists? The answer may lie in the ratios of D2 to D1 dopamine receptors in the developing brain.

The density of D1 receptors in the putamen increases after birth to a peak level around age 3, while the D2 density peaks around age 2. The density of D2 receptors falls after the peak, resulting in a 38% reduction by age 5 in most children. A high ratio of D2 to D1 densities in the age period between 3-5 may very well result in the stuttering evident in many children of this age group. Since D2 receptor density peaks earlier than the D1 density, the D2 to D1 density ratio may be high around the age of 3. In most children, the density ratio “normalizes” by age 5 leaving these children fluent, while this normalization process does not take place in children who go on to be persistent stutterers.

At the genomic level, there may be two types of genes related to stuttering. The first type may increase the risks of transient childhood stuttering, while the second type increases the risk of persistent stuttering. The effect of the two types of genes may be additive.

Direct/Indirect Pathways and Fluency

2011-06-19T08:00:00.005-04:00

In this post, we delve more deeply into the cortical-basal-ganglia-thalamus path (the circuit labeled by “1”) shown in the Figure in the previous post regarding the Dual Premotor System.

The particular components in the basal ganglia box of the aforementioned figure with which we deal here are the putamen and the globus pallidus (both the external, labeled GPe, and the internal, denoted GPi). These components are parts of what is called the corpus striatum.

In the Figure below, note that two types of dopamine receptors, namely D1 and D2, are involved in the putamen. There are 8 or 9 different dopamine receptors, but D1 and D2 are the dominant dopamine receptor subtypes in the putamen.

The direct pathway is activated by glutaminergic (glutamate is an excitatory neurotransmitter) projections from the sensorimotor area of the cortex and by dopaminergic projections from the substantial nigra to the D1 receptors. Activation of the direct pathway inhibits (via GABA) the globus pallidus internal (GPi) which in turn disinhibits the thalamus. As a consequence, the thalami-cortical drive is enhanced and cortically initiated speech will be facilitated.

The indirect pathway arises from the activation of D2 receptors in the putamen which stimulate GABA projections to the globus pallidus external (GPe) resulting in an inhibitory effect. This, in turn, disinhibits the subthalamic nucleus through GABA release. Glutamate projections from the subthalamic nucleus disinhibit the globus pallidus internal (GPi), which in turn inhibits the thalamus.

We see that the direct and indirect pathways act in opposite directions--the indirect pathway being the “brakes,” while the direct pathway is the “gas.” The direct pathway facilitates cortically initiated speech segments, giving a focused cue for the release of a motor segment. The indirect pathway provides a diffuse background of nerve impulse inhibition, suppressing potentially conflicting and unwanted speech motor patterns. The relative strengths of the two pathways determines the strength of the cortico-thalamic pathway. For fluent speech, a balance must exist between these two pathways.

If, for example, there were an excess of D2 receptors in the putamen, then the indirect path may dominate and a motor action associated with speech may be blocked from the cortico-thalamic pathway. In which case, that speech related motor action may be restarted, resulting in the repetitious pattern of stuttered speech characteristic of primary stuttering. On the other hand, a secondary stutterer may try to plow through the block to no avail--the signal necessary to execute the speech segment will simply be too weak.

The atypical antipsychotic drugs currently being prescribed for stuttering block D2 receptors and consequently reduce the negative impact of the indirect pathway.

Defending Covert Stuttering, Part 2

2011-06-01T19:29:00.001-04:00

If you are having a bad day with respect to fluency, consider talking less. Doing so may involve avoiding speaking situations within reason. This advice may be contrary to that given by most speech therapists.

Parkinson’s disease victims, like stutterers suffer from deficiencies with their dopaminergic systems. But their problem is too little dopaminergic activity rather than too much as in the case of stutterers. Like stutterers, Parkinson victims have good days with regard to motor function and bad days. They are generally advised to engage in physical activities on good days and take it easy on bad days when physical activity may be difficult.

So why should stutterers be treated differently from Parkinson’s victims? Covert stutterers may be mostly fluent but they also have their bad days when fluency is diminished. On such days it would be perfectly reasonable to engage in speech and situation avoidance behavior within limits.

What are these limits? If a Parkinson’s victim is having a bad day and his house is on fire, you would not advocate that he wait until he has a good day before he fled. Similarly, situations may occur whereby a stutterer should not go to extraordinary means to avoid speaking situations. For example, some social engagement for which you have a firm commitment should be kept. In a roomful of people, there are always several long-winded ones, and all you need to do is ask a question and they will happily launch into a 15 minute monologue. Linking together several of these people will easily occupy a cocktail hour with minimum speaking on your part.

Speech avoidance on a bad day is reasonable as long as you don’t do so out of a sense of embarrassment. Rather, you do so because speaking on a bad day is not fun. No matter how much you may think of yourself as a militant in-your-face overt stutterer (as a result of speech therapy), your limbic system (governing emotions) will still influence your fluency. Greater disfluency during bad days (along with negative emotional reactions at a subliminal level) may lead to an overall increased average level of disfluency. On the other hand, good experiences with respect to fluency may be expected to diminish disfluency over the long run.

Speech therapists should not advocate that a successful covert stutterer become an overt one. Instead, the focus should be on diminishing the involvement of the limbic system on the fluency problem. Doing so does not necessarily require that a stutterer stand on a soapbox in the middle of a mall declaring his disfluency.

Defending Covert Stuttering, Part 1

2011-05-17T01:52:00.000-04:00

It appears that one of the dogmas of most speech therapy approaches is to extinguish covert stuttering. Covert stuttering may involve behaviors such as substituting or omitting words, as well as circumlocution; yawns, coughs, or throat clearing may be used as well. In addition, avoidance behaviors may be present, such as choosing not to speak or entirely avoiding a situation that may involve speaking. In short, covert stuttering is regarded as an attempt to conceal stuttering.

Covert stuttering may be quite effective for individuals with relatively minor disfluency. Such individuals may appear to be perfectly fluent to most listeners. On the other hand, severe stutterers may not have the option to be covert.

According to most speech therapists, covert stuttering is a manifestation of embarrassment on the part of the stutterer. A goal of therapy is to desensitize the individual to his disability and to turn him into an overt stutterer.

On the stuttertalk website, two covert stutterers discuss their lives as coverts and are apologetic for their past behavior. See:

http://stuttertalk.com/2008/09/13/pam-and-sarah-covert-stuttering-episode-62.aspx

While I agree that one should strive to conquer the “embarrassment demon,” and effectively get control over one’s amygdala (see the posts on “An Anxious Mind Affects Stuttering”), I contend that it is not necessary to transform oneself into an overt stutterer. In many cases, giving oneself permission the stutter may result in a decrease of fluency. There is a modicum of mind control over one’s speech and ceding this control may actually increase stuttering.

Some speech therapy approaches involve voluntary stuttering--instead of ballgame, you say b-b-b-b-ballgame; similarly, prolonging a sibilant is regarded as acceptable. This is a form of substitution but at a syllabic level rather than a word level.

If you have trouble with s-words, for example, satellite, would a therapist be upset if you replaced the s with a ts-sound? What about replacing the “de” in the word decaffeinated with a rolled European r sound to give recaffeinated (instead of placing the tongue at the top of the upper teeth for the d-sound, gently roll the tongue across the roof of the mouth to get the European r)? Both of these substitutions are not that much different than the ballgame example, yet their upside is that you do not come off as a disfluent. So to take substitution to the extreme, is whole word replacement so bad (i.e., replacing teacher with instructor)?

An individual may choose to be covert for reasons other than avoiding embarrassment-- for example, a desire to communicate effectively. A job may require a certain level of fluency. A disfluent lawyer may be relegated to the “backroom,” but a covert stutterer would have the opportunity to practice the more people-oriented aspects of law.

It is simply much more fun to be a covert stutterer rather than an overt one.

Antipsychotic Drugs and Weight Gain

2011-05-05T19:17:00.000-04:00

For those individuals taking atypical antipsychotics (such as zyprexa, abilify, etc.) to improve fluency, weight gain as well as type-2 diabetes may be a problem. According to a single randomized controlled trial, metformin (an anti-diabetic drug) may reduce weight gain, in particular, when it is combined with lifestyle interventions such as dieting and exercise.

Reference:

Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA. 2008;299(2):185–93. doi:10.1001/jama.2007.56-b. PMID 18182600.

Stuttering Drug Research and the Social Media

2011-04-27T21:27:00.001-04:00

Social networking as a means for conducting drug testing was reported in the April 23, 2011 issue of the Wall Street Journal.

A clinical trial to test a drug for Amyotrophic Lateral Sclerosis (ALS) was conducted using social networking to enroll patients and collect data. The results were published in the online journal, Nature Biotechnology. This study, conducted by PatientsLikeMe, a health data sharing company, is an example of how social networking could play a role in the conduct of clinical trials and may be applicable to clinical trials for drugs affecting fluency.

Social network drug trials are not intended to replace conventional randomized double blind placebo controlled trials. However, such trials have become very time consuming and expensive and new drug testing models may be needed. Social network drug trials may have utility for the testing of off-label usage of various drugs that individuals might try to improve fluency but that may never arouse the (economic) interests of pharmaceutical companies. With the exception of pagoclone, which was never brought to market, the drugs tried for improving fluency (mainly atypical antipsychotics) have been previously used for other purposes.

The ALS study involved an online standardized collection of self-reported study participant data. The participants decided whether or not they would be taking the drug. PatientsLikeMe developed an algorithm to match study participants on the drug with at least one other participant not taking the drug in order to reduce the chance of false conclusions. The participants were able to see real-time data for groups and individuals on the website as the drug trial unfolded.

The social network approach took nine months to design, recruit, and present preliminary results, compared to about a year and a half for conventional trials.

Stuttering and the Brain Atlas

2011-04-20T19:38:00.001-04:00

A recent article in the Wall Street Journal (Wednesday, April 12, 2011) discussed the development of a comprehensive brain map, funded by Paul Allen, a cofounder of Microsoft. This computerized atlas of the human brain provides an interactive research tool to study the anatomy and the genes that underlie the mind and is freely available at

http://www.brain-map.org/

Specifically, the atlas provides a three dimensional interactive archive mapping overall brain anatomy at a high level of detail, nerve structure, cell features, and a comprehensive readout of gene activity. It may help researchers to understand the underlying brain biochemistry as well as where and how genes are at work in the brain. As such, it may provide clues to the root causes of neurological problems such as stuttering.

In the past, linking symptoms of a disease to the biochemistry of the genes that may be responsible for the disease had been very difficult. But the brain map identifies the location where a gene may be active in the brain, which is at the core for understanding how brain diseases work.

About 1000 anatomical landmarks had been catalogued for two normal adult brains (donated for research), which were then linked to the thousands of genes that act in complex combinations for normal neural development and function.

The researchers expect to add eight more brains to the database by the end of next year. It would be interesting to include brains of individuals suffering from various neurological ailments, including stuttering. Anyone wishing to contribute their brain should contact the Allen Institute for Brain Science in Seattle, Washington

Stuttering and the Dual Premotor System

2011-04-06T23:23:00.000-04:00

Although we discussed the medial and lateral premotor systems separately, they are part of an integrated motor function system known as the dual premotor system as shown in Figure 1. Loop 1 characterizes the medial premotor system, while loop 2 represents the lateral system.

The planning and initiation stages of speech originate in the cerebral cortex and the signals then pass through the basal ganglia back to the cerebral cortex via the supplementary motor area (SMA; not shown). The thalamus regulates the messaging to the SMA. This is the upstream loop for self-initiated, internally cued speaking situations.

For non-stutterers, the segments of motor activity (i.e., syllables), then pass unimpeded through the SMA and various other premotor areas, eventually reaching the cerebellum, which is a part of the downstream loop. On the other hand, stutterers experience impaired signaling in the area of the brain associated with the basal ganglia/SMA and neuronal signals are impeded from reaching the cerebellum.

Note that the inputs to the cerebellum from various regions of the cerebral cortex are more limited than the cerebral inputs to the basal ganglia as indicated by the smaller box within the larger one that denotes the cerebral cortex. The cerebellum promotes coordination and fine motor control of movement by influencing the output of brain motor systems to the peripheral nervous system (not shown in Fig. 1). To achieve this fine motor control, the cerebellum may be engaged in feedback control, going through several iterations in loop 2, modulated by sensory or other input.

As we indicated in the previous post, for certain activities such as chorus speaking, singing, altered auditory feedback, etc., loop 1 may be preempted, allowing the speaker to utilize only loop 2 which does not have the impairments associated with loop 1. Finally, note that there are limbic inputs (related to emotions) to loop 1, implying that emotional factors may further influence (perhaps negatively) the activity of this loop.

Stuttering and the Lateral Premotor System

2011-04-01T00:15:00.000-04:00

Individuals who stutter might be perplexed by their sudden fluency in certain contexts. For example, when speaking in unison as part of a chorus, they tend to be quite fluent. Similarly, fluency is enhanced when singing, speaking to the beat of a metronome, or consciously engaging in rhythmic monotonic speech. And the use of altered audio feedback devices improves fluency, at least temporarily.

Speech that is consciously controlled by role playing, imitating a foreign accent, or reducing the speech rate may also enhance fluency. Some individuals also observe that hyper-preparation for a public speaking engagement results in greater fluency by virtue of allowing for greater attention to the speech process; similarly, repeatedly reading a sentence in a clinical setting has been shown to improve fluency.

What all of these instances of enhanced fluency have in common is that the neural circuitry used in these situations circumvents the upstream medial premotor system (see the post on "Stuttering and the Medial Premotor System") which involves the basal ganglia as a timing mechanism. Instead of the medial premotor system, speech production is initiated further downstream by the lateral premotor system. This system involves only the cerebellum as the timing mechanism and, consequently, the faulty timing signals of the basal ganglia/SMA complex does not come into play.

A diagrammatic representation of the lateral premotor system is shown in Figure 1. Note that neural signals are passed from the lateral premotor cortex to the cerebellum, and from there to the arcuate premotor area (APA) in the cortex instead of the supplementary motor area (SMA) as was the case with the medial premotor system. Presumably, the dopamine receptor imbalance that may be present in the basal ganglia/SMA complex is absent from the neural circuitry of the lateral premotor system.

In the speaking contexts cited above, either the speech process relies on external timing cues or the cerebral cortex is relieved of certain planning and initiation actions. In either case, the circumvention of the neurally dysfunctional medial premotor system is facilitated and, instead, the lateral premotor system, operating in relation to sensory input, is directly activated.

On the other hand, the medial premotor system is brought into play for self-initiated, internally cued speaking situations. These situations reflect thoughts and emotions and involve the execution of automatized sequences of learned movements (i.e., speaking syllables of words) without attention. Consequently, such situations may lead to greater disfluency. Also, since there are limbic system inputs (i.e. the system relating to emotions) to the medial premotor system both at the cortical and basal ganglia levels, emotional responses may have an additional impact on fluency.

ITunes Podcasts on Stuttering

2011-03-25T15:45:00.001-04:00

I found a number of podcasts all available free on ITunes. I gather that most of these can be found also on the web. They include:

Stuttertalk.com by Peter Reties and Eric Jackson (165 episodes)

Stuttering is Cool by Daniele Rossi (114)

Stuttering 101 by the Stuttertalk people (26)

Stuttering Me by Greg@Stuttering.Me (39)

Make Room for the Stuttering by Pamela Mertz (50)

Stuttering John Smith (28)

In addition, you can buy the complete episodes of Porky Pig for about $20 or one episode entitled "The Case of the Stuttering Pig" for about $2.00. But it is questionable as to whether Porky was a stutterer--he may have been a clutterer or maybe even a stutterer/clutterer.

Is Gene Therapy for Stuttering Near?

2011-03-17T17:03:00.002-04:00

A fascinating article appearing in the Wall Street Journal ("Gene Therapy Raises Hopes for Parkinson's Treatment," March 17, p. A5) discusses a phase II trial for a Parkinson's gene therapy treatment. While in many ways, Parkinson's disease is the opposite of stuttering--too little dopamine vs. too much--the specific treatment may be applicable to stuttering.

Patients with Parkinson's also lose GABA. The therapy involves delivering a glutamic acid decarboxylase (GAD) gene to the bilateral subthalamic nuclei (STN) in the brain via an inert virus. The gene is responsible for making the chemical GABA and the therapy is said to improve motor function in Parkinson's victims.

Since some drugs such as benzodiazepines and pagoclone act to enhance the GABAergic system, it appears that the therapy cited above for Parkinson's might function also to increase GABA levels in people who stutter.

The controlled double blind phase II trials have been quite successful and Neurologix, Inc. is working with the USFDA to launch a phase III trial. And gene therapy for stuttering may be closer than you think.

A website providing more info can be found at:

www.fiercebiotech.com/story/neurologixs-gene-therpay-shows-parkinsons-promise/2011-03-17

A news release from Neurologix can be found at:

http://www.fiercebiotech.com/press-releases/neurologix-inc-therapy-lets-parkinson-patients-walk-carry-groceries

Stuttering and the Medial Premotor System

2011-03-17T15:22:00.007-04:00

In previous posts we have discussed the possible role of dopamine imbalances in the basal ganglia as a cause of stuttering. We now elaborate in greater detail as to how these imbalances may lead to disfluency by means of a model for speech production initially proposed by Van Riper and further elaborated by Per Alm.

Figure 1 is a schematic representation of the medial premotor system, the components of which are responsible for the production of speech. The medial premotor cortex (a part of the brain in the cerebral cortex responsible for the planning, selection and execution of actions) sends signals to the basal ganglia. These signals pass via neuronal pathways and are mediated by neurotransmitters.

In turn, the basal ganglia provides signals to the supplementary motor area (SMA). The SMA is an area in the cerebral cortex involved in actions under internal control, like the performance of a sequence of movements from memory. Speaking the syllables making up a word constitutes such a sequence.

The basal ganglia play a role in the initiation and regulation of motor commands. In particular, the basal ganglia system may very well contain the timer that influences the production of speech. Speech is a sequential motor task requiring exact timing and in order to execute each syllable, a "go" signal is required. The signal that is provided by the basal ganglia as a feed into the SMA cues the SMA to release the next segment (i.e., syllable) in the word sequence. Stuttering is viewed as a disruption of this sequencing of the syllables making up a word as a result of disturbed timing. If the signal is weak, then the next segment may not be released resulting in repetitions, haltings, and prolongations of the previous segment.

The neurotransmitter dopamine is the principal mediator of basal ganglia functions such as timing. The timing resulting from "normal" levels of dopamine is shown in Figure 2. A weak timing signal from the basal ganglia can occur in two ways. First, insufficient dopaminergic activity in the basal ganglia may lead to a weak signal feeding into the SMA, as shown in Figure 3.

Secondly, excessive levels of dopamine in the basal ganglia may result in an effectively weakened signal to the SMA due to noise drowning out much of the signal. This situation is shown in Figure 4. The "useful" part of the signal is that portion jutting above the noise and its amplitude is obviously diminished. Medications that reduce the level of dopaminergic activity and reduce the noise would be appropriate for this group of stutterers.

In both of these cases, the problem may originate either directly in the basal ganglia or, alternatively, through impaired inputs from the premotor area leading to an out of control basal ganglia with either a too weak signal or one attenuated by too much noise.

The medial premotor system, connecting the cerebral cortex to the basal ganglia, involves the nigrostriatal pathway. This pathway has close associations with the mesolimbic pathway (governing emotions), and because of this association, emotional states engendered by a particular context may influence motor activities such as those involving speech (see the previous "Anxious Brain" posts).

In a subsequent post, we will discuss the role of the lateral premotor system in the production of speech.

Neurofeedback and Stuttering

2011-03-09T13:25:00.002-05:00

Functional magnetic resonance imaging (FMRI) has provided insights into the possible neurological sources of stuttering. FMRI measures the change in blood flow as a result of neural activity in the brain and can document the active regions and functional activity of the brain at work in almost real-time. Evidence for the dopamine hypothesis of stuttering was provided by FMRI studies.

But FMRI has more recently been used to help individuals to control their brains through a neurofeedback mechanism. A cover article on "Understanding Pain," appeared in a recent issue of Time magazine (March 7, 2011). Specifically, subjects were given live access to an image of their brains' functional activity and were taught to control pain when a heat probe was applied to their arms. Their brains were essentially retrained to control the activation of neural pathways by targeting specific brain regions and processes.

The success of neurofeedback to control pain raises the question as to whether stutterers can cultivate the ability to control their brain processes so as to achieve greater fluency. Stuttering, being basically a mind/body problem, could possibly be amenable to such an approach. Dopaminergic pathways in both the motor neuron and the mesolimbic (governing emotions) sections of the brain might be controllable through neurofeedback mechanisms.

Anecdotal evidence that some individuals can control their fluencies to some extent has been discussed in a previous post (i.e., "Endogenously Reducing Dopamine"). It is interesting to speculate that these individuals may be engaging in some sort of neurofeedback at a subliminal level. In addition, certain aspects of speech therapy may informally and implicitly use neurofeedback (as well as biofeedback) approaches.

The exact mechanisms by which this fluency control is accomplished have not been identified. For example, whether dopaminergic activity is actually reduced or merely over-ridden is in question. However, with the use of FMRI, this question might be resolved and approaches developed whereby neurofeedback to improve fluency would be made available to a larger audience.

The use of FMRI has limitations with respect to the expense of the FMRI apparatus and the artificiality of the environment (i.e., lying on one's back and surrounded with noisy machinery) in which the subject would be placed.

A different method to study brain function is electroencephalography (EEG). Benefits of EEG compared to FMRI are that hardware costs are substantially lower, the machinery is less bulky and can be deployed in a wider variety of environments, and greater temporal resolution is enabled (on the order of milliseconds rather than seconds). In addition, the EEG is relatively tolerant of subject movement and is silent.

The limitations of EEG are that it has significantly lower spatial resolution and analyses of EEG results use relatively simple paradigms, compared with FMRI studies. Moreover, the EEG is most sensitive to postsynaptic potentials generated by the superficial layers of the cortex, namely the pyramidal neurons of the cortex because they are well-aligned and fire together. Voltage fields fall off with the square of the distance so activity from deep sources is more difficult to detect than currents near the skull. Thus, neuronal activity that emanates from the dorsal and ventral striata and the amygdala, potentially influencing fluency but deep within the brain, contribute far less to the EEG signal.

However, insofar as dopaminergic pathways and feedback loops exist between the deeper regions and the cortex, the measured EEG signals may contain information about the functioning of these deeper regions. An interesting study found at the URL,

www.bmedreport.com/archives/3138

claims to have identified potential EEG markers for stuttering based on comparing the EEGs of 26 children who stuttered with 21 age matched controls. Substantial differences in brain wave patterns exist between the two groups.

In summary, it appears that further explorations of neurofeedback mechanisms to ameliorate disfluency might be warranted, one of the major advantages being the elimination or reduction of the use of drugs.

The King's Speech Inspiration

2011-03-04T12:54:00.000-05:00

Here is the URL for another New York Times article inspired by "The King's Speech."

http://cityroom.blogs.nytimes.com/2011/03/03/relearning-speech-to-make-it-cushiony-not-jagged/?ref=todayspaper

Impact of EXPRESS Pagoclone Trial Group Inhomogeneities

2011-03-01T13:47:00.003-05:00

In the published results of the EXPRESS (EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study) pagoclone trials*, the pagoclone group and the placebo group were inhomogeneous with respect to at least one characteristic. Specifically, the mean social anxiety of the groups as measured by the Liebowitz Social Anxiety Scale (LSAS) differed--the pagoclone group measured 46, while the placebo group scored 56. So the placebo group tended to have a higher degree of social anxiety.

Given that stuttering is both a function of the brain as well as the mind (anxiety being a mind state), we can attempt on a priori grounds to determine the direction of potential bias of the LSAS inhomogeneity with respect to trial outcomes.

One question that arises concerns a potential relationship between social anxiety and suggestibility. Might individuals with high levels of social anxiety be more suggestible? For example, a high anxiety individual might be more strongly motivated to hope or believe in a placebo's positive outcome if only as a relief from the discomfort of an anxious mind. If this were the case, a placebo might have a stronger effect on the higher anxiety placebo group and the difference of the fluency outcomes between the pagoclone and placebo groups would be narrowed. Thus, the efficacy of pagoclone, as measured by the extent that fluency is improved beyond the placebo response, might be biased downward (i.e., underestimated). In addition, the significance level associated with the outcome might also be reduced.

Even if there were no significant correlation between social anxiety and suggestibility, the placebo group, having the higher average LSAS score, might be more responsive to a placebo. In the several previous posts on "The Anxious Mind Affects Stuttering," we emphasized that stuttering is not only a physiological problem associated with the brain, but also a mind problem. A placebo tends to be particularly efficacious for the mind portion of a mind/body problem such as stuttering. So, if this were the case, we might again expect pagoclone efficacy to be underestimated.

The problem of group inhomogeneities is endemic to ANOVA types of analyses, such as was performed in the pagoclone EXPRESS study. Granted that the group numbers in this study were relatively small, but even for larger trials various inhomogeneities may still be a problem.

A possible resolution to this problem might be the use of regression analysis approaches of the type suggested in two of the recent posts discussing a proposal for the analysis of pagoclone trials. The units of observation become the individuals participating in the trial rather than the groups, and the LSAS can be used as an additional explanatory variable in any of the models suggested in those posts. For example, a logarithmic model might be (ignoring the suggestibility variable):

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

where the variables DFA, DFB, and T were defined in the post, "A Proposal for Analyzing Pagoclone Trials." In addition, non-linear effects of the LSAS can be explored by entering quadratic terms as well as cross products of LSAS with the other explanatory variables in the model.

* G. Maguire, et al, Journal of Clinical Psychopharmacology (Feb. 2010), pp. 48-56, Vol. 30, Number 1.

(copyright 2011)

Stuttering, Movies, and Research

2011-02-26T12:47:00.000-05:00

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

2011-02-22T22:25:00.001-05:00

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

2011-02-10T22:21:00.000-05:00

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

2011-02-09T15:12:00.000-05:00

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

2011-02-02T11:14:00.002-05:00

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

2011-01-27T19:26:00.000-05:00

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

2011-01-24T00:28:00.000-05:00

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

2011-01-16T12:37:00.001-05:00

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

2011-01-11T16:18:00.000-05:00

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

2010-12-20T13:26:00.003-05:00

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

2010-12-19T04:56:00.001-05:00

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?

2010-12-16T01:09:00.001-05:00

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?

2010-12-11T16:14:00.001-05:00

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

2010-12-05T14:01:00.000-05:00

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

2010-11-30T18:26:00.000-05:00

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

2010-11-26T10:15:00.002-05:00

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

2010-11-21T20:14:00.000-05:00

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

2010-11-16T17:45:00.001-05:00

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

2010-11-14T01:08:00.005-05:00

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

2010-11-11T06:23:00.002-05:00

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

2010-10-22T18:23:00.001-04:00

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

2010-10-16T15:56:00.000-04:00

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

2010-10-08T19:05:00.000-04:00

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

2010-10-04T18:51:00.000-04:00

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

2010-09-26T15:57:00.002-04:00

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

2010-09-22T15:14:00.000-04:00

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

2010-09-16T17:26:00.000-04:00

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

2010-09-08T21:35:00.001-04:00

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

2010-09-04T18:30:00.003-04:00

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

2010-08-25T22:59:00.001-04:00

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

2010-08-14T21:15:00.000-04:00

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

2010-08-09T18:14:00.001-04:00

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.

Stuttering, Placebos, and Nocebos

2010-08-03T18:18:00.000-04:00

A placebo is a sham medical intervention that may produce a therapeutic effect in a patient. For example, an inert pill can be administered with the suggestion that it may improve the patient's condition. The result, called the placebo effect, is an excellent example of how the mind can affect a physiological reaction and the impact of positive expectations on biological outcomes.

There are also placebo-like effects whereby no physical placebo is administered, the effect being due to the influence of a specific context on the patient's mind (e.g. verbal suggestions of improvement). Regardless of the exact nature of the placebo, expectation of a future outcome is a principal mechanism for the placebo effect.

Also, a conditioned neutral stimulus (e.g., the color of a sham pill) can become a placebo if it is repeatedly associated with an unconditioned stimulus (e.g., the drug inside a real pill). Therefore, a patient who is initially given a real pill and is subsequently switched to a sham pill of the same shape and color may continue to show therapeutic effects. Conditioning leads to the expectation that one event will follow another event on the basis of the information that the conditioned stimulus provides about the unconditioned stimulus. This is called the conditioned response model.

On the other hand, nocebos are essentially the opposite of placebos in that nocebos may lead to negative pathological effects. Beliefs and expectations may sicken or kill, as in the extreme case of voodoo deaths. Negative expectation inducing events or procedures may lead to symptom worsening. The fear/avoidance model of pain can be viewed as a kind of noceba-like effect, whereby the fear of pain may lead to the worsening of pain. As with placebos, we might also expect that nocebos could exhibit a conditioned response mechanism. And this is where nocebos may play a role in stuttering.

A stutterer may have had embarrassing experiences in a given context with his speech (e.g., speaking in front of an audience); this is the conditioned stimulus. Since this stimulus is repeatedly associated with the stuttering, conditioning will lead to the expectation that stuttering will follow standing before an audience. The noceba effect offers a rationale for the diagram shown in the blog posting entitled "Stuttering, the Mind, the Body," in that a context (e.g., public speaking) can result in a worsening of one's fluency.

More on Mind/Body Connection

2010-07-27T00:16:00.000-04:00

Disfluency is a combination of brain disfunction and mind involvement. The usual standard for judging stuttering severity is the number of disfluencies experienced over a given tIme period when reading, for example, a given amount of text. But the severity of stuttering gives no indication of the extent of brain involvement in the episode given that the mind and the context also come into play. In the ideal, we would like to rank the brain involvement on a scale from 1 to 10, where 1 is the least severe and 10 is the most severe. Similarly, the mind involvement can also be ranked on a 1 to 10 scale. So the most severe episode of stuttering would have a score of 20, while the least severe would be scored a 2. An individual may have intense brain involvement with a score of 10, yet not be very reactive and have a mind involvement score of 1, for a total of 11. Another person may have a mild brain involvement with a score of 1, yet be very reactive with a mind involvement score of 10, again for a total of 11. In both cases, the severity of stuttering may be the same, but the underlying causes would be different. And each of these cases may respond differently to treatment. For example, the person with greater mind involvement might respond better to psychologically based therapies while those with substantial brain involvement would show better improvement with drug therapies.

Unfortunately, it would be very difficult to disentangle the brain involvement from the mind involvement on a priori grounds. A clinician might be able to infer the relative amounts of involvement only after observing treatment results.

Stuttering, the Mind, and the Body

2010-07-21T16:04:00.000-04:00

There are many ailments that start as a problem with some part of the body but are made worse when the mind comes into play. Knee or back pain may have its roots in some physical problem with one's bones, ligaments, or tendons and this may cause some discomfort or pain. But in some individuals, the mind comes into play and this discomfort or pain becomes intensified. Another example is erectile disfunction, which may initially have some physiological roots, start out as relatively mild, but through repeated embarrassing failures end up as a more intense problem. This phenomenon is called the mind/body connection.

It turns out that stuttering has a strong mind/body connection for most people with this problem. It is currently believed that in the great majority of cases stuttering starts in a preschool child because of a malfunction in the motor neuron section of the brain. At this point in time the child is relatively unaware of the problem, but by the time he reaches school age, parents reacting negatively and teasing schoolmates make him acutely aware. What happens at this point is that the mind comes into play resulting in secondary stuttering characteristics such as blocking, twitching, etc. So the initial fluency problem is intensified by the action of the mind. This mind/body connection (the body part involved being the brain) can be depicted in the diagram below:

Starting from the left, some root cause--in the case of stuttering an abnormality in the brain--leads to a physical problem, namely stuttering. This physical problem results, at some point, in anxiety which may vary depending upon the context in which the stutterer finds himself (e.g., speaking before an audience). This anxiety then feeds back into the physical problem, perhaps making the stuttering worse. So the physical problem is in some sense the product of a body problem (in this case the brain) and a mind problem (in this case the awareness and the anxiety associated with stuttering.

INTRODUCTION

2010-07-17T03:22:00.000-04:00

This blog is dedicated to exploring stuttering and its connection to both the mind and the body. Future posts will provide information about the current understanding of the causes of stuttering, e the role of the brain in stuttering, as well as the role of the mind. The mind is distinguished from the brain in that the brain is the physical mass that exists in your skull, while the mind is a manifestation of the brain (e.g., consciousness and self-awareness). In addition, future posts will deal with the role of drugs in treating stuttering, drug trials, and their interpretation.

Many of the readers of this blog had high hopes for the recent pagoclone drug trials, but recently the pharmaceutical company, Indevus, announced the termination of these trials. There could be many reasons for this termination, one of which is that the drug did not perform statistically better than a placebo (i.e., a sugar pill). Another possibility is that the drug did not live up to other "success criteria" set up for it. For example, a user of the drug may develop a tolerance for a given dosage (this is common for tranquilizers) and that dosage may subsequently become ineffective for improving fluency.

At any rate, a number of test subjects in the pagoclone trials have reported extended fluency improvements while on pagaclone and decreased fluency while on the placebos. So we can await future announcements from the drug company as to the reasons that the trials have stopped.

So tune in for future posts on this blog. I'm sure that you will find them to be educational and informative.