Sunday, June 19, 2011

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.


Gerald Maguire, MD said...

Very clear description. Thank you for your informative blog.

Anonymous said...

reviewing medications i tried both risperidone and olanzipine, both proved to be ineffective.

the only help was the slight sedation but did not help in more stressful situations such as phone, interviews. i tried both at weekly incresing doses up to max 5mg.

My speech is characterised more so by specific blocks does this mean that is more likely gaba pathways?

stutter-mind-body said...

Assuming that you did not spontaneously hit a particularly severe disfluency period while taking the drugs (so that the drug effect was to bring you back to "average" disfluency), there are some individuals that do not respond to atypical antipsychotics. With respect to GABA channels, taking BZs is only an indirect way of inhibiting dopaminergic activity. More on atypical antipsychotic resistant stuttering in a future post.