Hypothesis

Combining a chronically administered low‑impact ampakine (e.g., CX1739) with an NMDA‑receptor‑dependent metaplastic priming protocol (such as intermittent theta‑burst stimulation, iTBS) will selectively rescue long‑term potentiation (LTP)–like synaptic plasticity in the dorsolateral prefrontal cortex (dlPFC) of healthy older adults, leading to measurable improvements in working memory capacity.

Mechanistic Rationale

• AMPAR potentiation without desensitization: Low‑impact ampakines bind the GluA2/GluA3 dimer interface, reducing AMPAR deactivation and thereby increasing the probability of synaptic transmission during high‑frequency activity [1]. Chronic low dosing avoids the receptor overload that produced adverse events with high‑impact ampakines (e.g., S18986).
• NMDA‑dependent metaplastic priming: iTBS induces a transient rise in intracellular Ca2+ via NMDA receptors, shifting the synaptic modification threshold toward LTP (a metaplastic state) [2]. This priming does not itself cause lasting change but makes synapses more receptive to subsequent AMPAR‑mediated potentiation.
• Synergistic timing: Administering the ampakine 30 min after each iTBS session ensures elevated AMPAR conductance coincides with the metaplastic window, amplifying calcium‑independent signaling pathways (e.g., CaMKII autophosphorylation) that underlie LTP consolidation.
• Regional specificity: Targeting dlPFC with neuronavigated iTBS leverages its role in working memory; AMPAR effects are globally expressed but behavioral readouts will be strongest where priming occurs.

Testable Predictions

1. Neurophysiological: In a double‑blind, crossover study, participants receiving iTBS + low‑dose CX1739 will show a ≥15 % increase in paired‑pulse facilitation‑adjusted LTP‑like plasticity measured via transcranial magnetic stimulation (TMS)–evoked EEG markers compared with iTBS + placebo or CX1739 + sham iTBS (p < 0.05, FDR‑corrected).
2. Cognitive: Working memory performance (n‑back accuracy, 3‑back) will improve by ≥0.5 SD relative to baseline only in the combined condition, with no significant change in either monotherapy.
3. Safety: No increase in adverse event rates beyond mild headache or transient scalp discomfort; vital signs and routine labs remain within normal limits across 4‑week treatment.

Falsifiability

If the combined intervention fails to produce a statistically significant LTP‑like enhancement over either monotherapy, or if working‑memory gains are absent despite physiological changes, the hypothesis is falsified. Conversely, a selective effect only in the combined arm supports the mechanistic claim that NMDA‑dependent metaplastic priming is required to translate chronic AMPAR potentiation into functional cognitive improvement in aging.