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