NMDA Receptor Hypofunction in Stuttering: A Proposed Unifying Hypothesis and Implications for Glycine-Based Interventions

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.