Tuesday, November 30, 2010

An Anxious Mind Affects Stuttering, Part 2

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


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

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

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

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

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

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

Friday, November 26, 2010

An Anxious Mind Affects Stuttering, Part 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sunday, November 21, 2010

Drug Dosages and Additional Drug Candidates

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


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


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

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

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

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

Tuesday, November 16, 2010

Using Drugs to Improve Fluency

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

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

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

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

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

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

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

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

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

Sunday, November 14, 2010

Further Drug Research

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

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

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

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

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

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

Thursday, November 11, 2010

Rationale for this Blog

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


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


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