Stuttering is a complex neurological disorder arising from deficits in the motor control network connecting the cerebral cortex and the basal ganglia 3, 6. Existing pathophysiological research has predominantly relied on the hyperdopaminergic hypothesis; however, it is increasingly suggested that this may be the result of a downstream cascade rather than the singular root cause of the disorder 5, 7. This paper proposes the NMDA receptor hypofunction model as a novel unifying hypothesis to explain speech fluency disorders. It is postulated that when NMDA receptors on inhibitory parvalbumin-positive (PV+) interneurons in the cerebral cortex become compromised, the cortical network experiences disinhibition, leading to a surge of glutamate that disrupts the downstream dopaminergic system in the basal ganglia 28, 35. Consequently, the basal ganglia fail to generate the "Go-signals" (timing cues) essential for speech initiation, which can result in the physical "blocks" of the articulatory organs 21, 25. This hypothesis regarding a plausible upstream mechanism is supported by clinical cases of drug-induced stuttering (DIS), where the NMDA receptor antagonist memantine provoked severe speech initiation deficits in previously fluent pediatric patients 10, 11, as well as by recent magnetic resonance spectroscopy (MRS) data revealing excitatory/inhibitory (E/I) imbalances in speech control regions 45. Drawing upon analogies from schizophrenia research and preliminary clinical observations, this study presents a high-dose glycine administration protocol (approximately 0.8 g/kg) as a potential therapeutic avenue 51, 56. This protocol relies on passive diffusion to penetrate the blood-brain barrier (BBB) and saturate the co-agonist binding site (GlyB site) of the NMDA receptor 17, 52. This model provides a biochemical foundation for expanding the paradigm of stuttering treatment from downstream dopamine suppression to the restoration of upstream network synchronization. However, for the co-agonist therapy proposed in this paper to be established as a standard clinical treatment, it is imperative that its safety and efficacy are validated through rigorous randomized controlled trials (RCTs) involving individuals who stutter.
권준수 (Fri,) studied this question.