Chronic neuropathic pain presents a major challenge to pharmacological therapy and neurostimulation-based alternatives are gaining interest. Although invasive and non-invasive motor cortex stimulation has been the focus of several studies, very little is known about the potential of targeting the prefrontal cortex. This study was designed to elucidate the analgesic potential of prefrontal stimulation in a translational context and to uncover the neural underpinnings thereof.

Here, we report that non-invasive, repetitive direct anodal current transcranial stimulation (tDCS) of the prefrontal cortex exerted analgesia in mice with neuropathic pain for longer than a week. When applied at chronic stages of neuropathic pain, prefrontal tDCS reversed established allodynia and suppressed aversion and anxiety-related behaviours. Activity mapping as well as in vivo electrophysiological analyses revealed that although the cortex responds to acute tDCS with major excitation, repetitive prefrontal tDCS brings about large-scale silencing of cortical activity. Different classes of different classes of GABAergic interneurons and classes of excitatory neurons differs dramatically between single, acute vs and repetitive tDCS. Repetitive prefrontal tDCS alters basal activity as well as responsivity of a discrete set of distant cortical and sub-cortical areas to tactile stimuli, namely the rostral anterior cingulate cortex, the insular cortex, the ventrolateral periaqueductal grey and the spinal dorsal horn.

This study thus makes a strong case for harnessing prefrontal cortical modulation for non-invasive transcranial stimulation paradigms to achieve long-lasting pain relief in established neuropathic pain states and provides valuable insights gained on neural mechanistic underpinnings of prefrontal tDCS in neuropathic pain.

慢性神经性疼痛对药物治疗提出了重大挑战，基于神经刺激的替代方案正在引起人们的兴趣。尽管侵入性和非侵入性运动皮层刺激一直是几项研究的重点，但对针对前额叶皮层的潜力知之甚少。本研究旨在阐明前额刺激在翻译环境中的镇痛潜力，并揭示其神经基础。

在这里，我们报告前额叶皮层的非侵入性、重复性直接阳极电流经颅刺激 (tDCS) 对患有神经性疼痛的小鼠的镇痛作用超过一周。当应用于神经性疼痛的慢性阶段时，前额叶 tDCS 可逆转已建立的异常性疼痛并抑制厌恶和焦虑相关的行为。活动映射以及体内电生理分析表明，尽管皮层对急性 tDCS 的反应主要是兴奋，但重复的前额叶 tDCS 会导致皮层活动的大规模沉默。不同类别的不同类别的 GABAergic 中间神经元和兴奋性神经元类别在单个、急性与重复 tDCS 之间存在显着差异。

因此，这项研究为利用前额叶皮层调节进行无创经颅刺激模式以在已建立的神经性疼痛状态下实现持久的疼痛缓解提供了强有力的案例，并为神经性疼痛中前额叶 tDCS 的神经机制基础提供了有价值的见解。