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.

Neurofeedback and Stuttering

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

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

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

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

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

Entanglement of Dopamine, Serotonin, and GABA Systems

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

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

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

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

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

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

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

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

An Alternative to The King's Speech

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

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

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

More on Proposed Pagaclone Trial Analysis

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


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

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

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

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

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

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

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

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

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

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

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

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

(Copyright 2011)

A Proposal for Analyzing Pagoclone Trials

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Copyright 2011)

Placebos, Suggestibility, and Hypnosis

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


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

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

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

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

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

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

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

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

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

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

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

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

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