Wednesday, August 25, 2010

Stuttering and Neurotransmitters

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

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

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

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

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

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

Saturday, August 14, 2010

Stuttering and Dopamine

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

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

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

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

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

Monday, August 9, 2010

Parkinson's Disease, Dopamine, and Stuttering

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

Victims of Parkinson's disease have a deficit of dopamine activity in the same area of the brain in which stutterers have an overabundance. And an interesting observation is that Parkinsonism patients receiving a placebo showed a substantial increase of dopamine activity in this part of the brain according to brain imaging results. So we can wonder if, similarly, the nocebo-like effect of context on stuttering might also increase the level of dopamine activity in the brains of stutterers, thus negatively affecting their fluency.
The diagram discussed in the blog entry entitled "Mind/Body Problem" is repeated here with the specific labels related to stuttering replacing the generalized labels of the previous diagram.  Note that the "Anxiety" label was replaced with the "Mind" label since anxiety can be viewed as a state of the mind.  So basically, stuttering affects the mind (i.e., causes anxiety) which in turn affects stuttering.  In addition, the context (e.g., speaking before an audience), through conditioning, further affects the mind and the subsequent lack of fluency.
However, given the possible dopamine connection discussed above, we can modify the diagram as follows:

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

Tuesday, August 3, 2010

Stuttering, Placebos, and Nocebos

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

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

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

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

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