Brain Imaging and Stuttering

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

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.

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*  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

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?

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

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

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.

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*  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

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

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.

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*  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?

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

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

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

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.

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* 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

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.

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* 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

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

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.

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

Subgroups of Stutterers

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.

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* 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

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 
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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

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

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

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

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

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

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

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

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

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

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?

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

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.