Friday, July 22, 2011

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.


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

Saturday, July 9, 2011

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.


* 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:

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

Friday, July 1, 2011

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 


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.