Caffeine, a widely consumed psychostimulant, has long been recognized for its impact on adenosine receptors, particularly as a competitive antagonist of the A1 and A2A subtypes. The intricate interplay between caffeine and long-term potentiation (LTP) has been a subject of scientific inquiry, especially in the context of its effects on synapses and neuropsychiatric disorders.
This article delves into the complex relationship between caffeine and human brain plasticity, exploring the findings of key studies and shedding light on the potential implications for repetitive transcranial magnetic stimulation (rTMS) in neuropsychiatric treatment.
Adenosine Receptor Antagonism and Synaptic Plasticity:
The A1 receptor antagonism induced by caffeine has been associated with the strengthening of synapses through LTP, while A2A antagonism appears to have the opposite effect by attenuating LTP (1). This intricate mechanism sets the stage for understanding the impact of caffeine on the plasticity of the human brain.
rTMS as a Tool for Investigating Brain Plasticity:
Repetitive transcranial magnetic stimulation (rTMS) has emerged as a valuable tool for treating neuropsychiatric disorders, with its therapeutic effects postulated to be linked to LTP. Through animal and human studies, the influence of rTMS on brain plasticity has been explored, providing insights into its potential as a treatment modality (2–6). Furthermore, the integration of electromyography (EMG) recordings with rTMS allows for the measurement of corticomotor excitability through motor evoked potentials (MEPs), providing a window into the underlying neural plasticity (7, 8).
Human Studies on Acute Caffeine Intake and LTP-like Effects:
Despite the recognized benefits of caffeine on memory rescue and LTP, recent human studies have uncovered a paradoxical relationship between acute caffeine intake and LTP-like after-effects induced by brain stimulation protocols. In one study utilizing quadripulse TMS, subjects exhibited robust potentiation in response to placebo stimulation but experienced blunted responses when exposed to 200 mg of caffeine plus quadripulse stimulation (10). Another study, employing espresso administration and transcranial alternating current stimulation (tACS), revealed that decaffeinated espresso blunted facilitation, while caffeinated espresso actually reversed it (11). The intriguing question of whether these opposing effects are mediated by the A2A receptor or downstream mechanisms remains unanswered.
Chronic Caffeine Consumption and Neural Plasticity:
Discussion
The present study aimed to investigate the impact of chronic caffeine use on excitatory plasticity, focusing on the combination of d-cycloserine (DCS) with 10 Hz repetitive transcranial magnetic stimulation (rTMS). Contrary to the initial hypothesis, our findings revealed a robust facilitation of motor evoked potentials (MEPs) in non-caffeine users (NCU) when exposed to DCS combined with 10 Hz rTMS. Surprisingly, this facilitation was significantly attenuated in caffeine users (CU), bringing their response level to that observed in the placebo condition for both groups (Figure 1A). These results imply a potential impairment in long-term potentiation (LTP)-like plasticity in chronic caffeine users.
It is crucial to acknowledge the limitations of our study, particularly the small sample size of NCU (four subjects) compared to CU (16 subjects). This discrepancy may overestimate the effect size and calls for caution in drawing definitive conclusions. Future studies could address this limitation by recruiting well-matched groups in terms of age, education, and socioeconomics to enhance statistical power.
The reliance on self-reported caffeine dosages, consistency, and regularity introduces another limitation, preventing the creation of a dose-response curve based on caffeine bioavailability during experimentation. Estimating an average daily consumption of 137 mg/day with a range of 30-270 mg/day based on previous trials, we suggest that future research should incorporate caffeine serum concentration assessments to improve precision and correlate with plasticity responses.
Despite these limitations, our study offers a unique perspective on the potential mechanisms underlying the observed effects. The blunted plasticity in caffeine users raises questions about the involvement of adenosine A2A receptors, as A2A antagonism is known to attenuate LTP.
However, the overall effects of caffeine remain complex, with opposing outcomes reported in the literature. Examining the role of intracellular calcium, mobilized by caffeine, may shed light on the observed plasticity effects. Chronic caffeine intake may lead to modest calcium levels, complicating the speculation about its interplay with plasticity induced by rTMS.
Our study also prompts considerations about the duration of rTMS-mediated plasticity, as we measured responses up to 1 hour, while some studies report LTP-like after-effects lasting more than 24 hours. Investigating the persistence of these effects and their correlation with AMPA receptor insertion and spine expansion observed in animal models could provide a more comprehensive understanding.
In conclusion, our study suggests that chronic caffeine use may attenuate excitatory plasticity, contrasting with the robust facilitation observed in non-caffeine users. While the study design and the small number of non-caffeine users limit the strength of our conclusions, these findings may inform future research and dosage considerations.
Furthermore, the potential impact of caffeine on clinical rTMS responses remains an intriguing avenue for exploration, considering the observed interindividual variability in MEP plasticity and the proposed mechanistic basis provided by caffeine in our pilot studies. As caffeine is widely consumed, unraveling its influence on the mechanisms of learning and memory, as well as its potential impact on clinical rTMS effects, warrants further investigation.
reference link : https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1137681/full
