Transcranial direct current stimulation (tDCS) has garnered significant interest for its potential to enhance cognitive functions and as a therapeutic intervention in various cognitive disorders. However, the clinical application of tDCS has been hampered by significant variability in its cognitive outcomes. Furthermore, the widespread use of tDCS has raised concerns regarding its safety and efficacy, particularly in light of our limited understanding of its underlying neural mechanisms at the cellular level. We still do not know ‘where’, ‘when’ and ‘how’ tDCS modulates information encoding by neurons, in order to lead to the observed changes in cognitive functions. Without elucidating these fundamental unknowns, the root causes of its outcome variability and long-term safety remain elusive, challenging the effective application of tDCS in clinical settings. Addressing this gap, our study investigates the effects of tDCS, applied over the dorsolateral prefrontal cortex, on cognitive abilities and individual neuron activity in macaque monkeys performing cognitive tasks. Like humans performing a delayed match-to-sample task, monkeys exhibited practice-related slowing in their responses (within-session behavioural adaptation). Concurrently, there were practice-related changes in simultaneously recorded activity of prefrontal neurons (within-session neuronal adaptation). Anodal tDCS attenuated both these behavioural and neuronal adaptations when compared with sham stimulation. Furthermore, tDCS abolished the correlation between response time of monkeys and neuronal firing rate. At a single-cell level, we also found that following tDCS, neuronal firing rate was more likely to exhibit task-specific modulation than after sham stimulation. These tDCS-induced changes in both behaviour and neuronal activity persisted even after the end of tDCS stimulation. Importantly, multiple applications of tDCS did not alter burst-like firing rates of individual neurons when compared with sham stimulation. This suggests that tDCS modulates neural activity without enhancing susceptibility to epileptiform activity, confirming a potential for safe use in clinical settings. Our research contributes unprecedented insights into the ‘where’, ‘when’ and ‘how’ of tDCS effects on neuronal activity and cognitive functions by showing that modulation of the behaviour of monkeys by the tDCS of the prefrontal cortex is accompanied by alterations in prefrontal cortical cell activity (‘where’) during distinct trial phases (‘when’). Importantly, tDCS led to task-specific and state-dependent alterations in prefrontal cell activities (‘how’). Our findings suggest a significant shift from the view that the effects of tDCS are merely attributable to polarity-specific shifts in cortical excitability and instead propose a more complex mechanism of action for tDCS that encompasses various aspects of cortical neuronal activity without increasing burst-like epileptiform susceptibility.

中文翻译：

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直流电刺激可调节前额叶细胞的活动和行为，而不会诱导癫痫样放电


经颅直流电刺激 （tDCS） 因其增强认知功能和作为各种认知障碍的治疗干预的潜力而引起了人们的极大兴趣。然而，tDCS 的临床应用受到其认知结果的显着差异的阻碍。此外，tDCS 的广泛使用引起了对其安全性和有效性的担忧，特别是鉴于我们对细胞水平上其潜在神经机制的了解有限。我们仍然不知道 tDCS 的“位置”、“时间”和“如何”调节神经元的信息编码，以导致观察到的认知功能变化。如果不阐明这些基本的未知因素，其结果可变性和长期安全性的根本原因仍然难以捉摸，对 tDCS 在临床环境中的有效应用提出了挑战。为了解决这一差距，我们的研究调查了应用于背外侧前额叶皮层的 tDCS 对执行认知任务的猕猴认知能力和个体神经元活动的影响。就像人类执行延迟的匹配样本任务一样，猴子的反应也表现出与实践相关的减慢（会话内行为适应）。同时，同时记录的前额叶神经元活动 （会话内神经元适应） 存在与实践相关的变化。与假刺激相比，阳极 tDCS 减弱了这些行为和神经元适应。此外，tDCS 消除了猴子响应时间与神经元放电率之间的相关性。在单细胞水平上，我们还发现 tDCS 后，神经元放电率比假刺激后更有可能表现出任务特异性调节。 即使在 tDCS 刺激结束后，这些 tDCS 诱导的行为和神经元活动变化仍然存在。重要的是，与假刺激相比，tDCS 的多次应用并没有改变单个神经元的爆发样放电率。这表明 tDCS 在不增强对癫痫样活动的敏感性的情况下调节神经活动，证实了在临床环境中安全使用的潜力。我们的研究通过表明前额叶皮层的 tDCS 对猴子行为的调节伴随着前额叶皮层细胞活动（“在哪里”）的改变，在不同的试验阶段（“时间”）。重要的是，tDCS 导致前额叶细胞活动（“如何”）的任务特异性和状态依赖性改变。我们的研究结果表明，tDCS 的影响仅归因于皮层兴奋性的极性特异性变化的观点发生了重大转变，而是提出了一种更复杂的 tDCS 作用机制，该机制涵盖了皮层神经元活动的各个方面，而不会增加爆发样癫痫样易感性。