Jones Martyn G, Matthews Liam A, Lempka Scott, Verma Nishant, Harris James P, McMahon Stephen B
Wolfson Sensory, Pain and Regeneration Centre, King's College London, London, United Kingdom.
Zenith Neurotech Ltd., King's College London, London, United Kingdom.
Front Neurosci. 2025 Jan 17;18:1512950. doi: 10.3389/fnins.2024.1512950. eCollection 2024.
Many forms of chronic pain remain refractory to existing pharmacotherapies and electrical neuromodulation. We have recently reported the clinical efficacy of a novel form of analgesic electrical neuromodulation that uses ultra low frequency (ULF) biphasic current and studied its effects on sensory nerve fibers. Here, we show that in anesthetized rats, epidural ULF current reversibly inhibits activation of neurons in the thalamus receiving sensory spinothalamic input.
In naïve, neuropathic and sham-operated rats, recordings of ongoing and evoked activity were made from thalamic neurons, targeting the ventral posterolateral (VPL) nucleus.
Responses to electrical stimulation of hind limb receptive fields were reduced in 25 of 32 (78%) neurons tested with lumbar epidural ULF neuromodulation. Cells preferentially responsive to low intensity stimulation were more likely to be found than cells responding to a range of stimulus intensities, or high intensity only; and low threshold responses were more likely to be inhibited by ULF than high threshold responses. On-going activity unrelated to hindlimb stimulation, observed in 17 of 39 neurons in naïve animals (44%), was reduced by lumbar epidural ULF current in only 3 of 14 (21%) neurons tested with ULF. By contrast, in rats with a well-characterized neuropathic injury, spinal nerve ligation (SNL), we found a much higher incidence of on-going activity in thalamic neurons: 53 of 55 neurons (96%) displayed firing unrelated to hindlimb stimulation. In this group, ULF current reduced thalamic neurone discharge rate in 19 of 29 (66%) neurons tested. In sham-operated animals, the incidence of such activity in thalamic neurons and the effect of ULF current were not significantly different from the naïve group.
We conclude firstly that ULF current can acutely and reversibly interrupt signaling between sensory afferent fibers and relay neurons of the thalamus. Second, ongoing activity of thalamic neurons increases dramatically in the early stages following neuropathic injury. Third, this novel form of neuromodulation preferentially attenuates pathological thalamic activity in this neuropathic model compared to normal activity in naïve and sham-operated animals. This study, therefore, demonstrates that epidural ULF current can reduce nerve injury-related abnormal activity reaching the brain. These findings help advance understanding of possible mechanisms for the analgesic effects of ULF neuromodulation.
许多形式的慢性疼痛对现有的药物治疗和电神经调节仍具有抗性。我们最近报道了一种新型镇痛电神经调节的临床疗效，该调节使用超低频（ULF）双相电流，并研究了其对感觉神经纤维的影响。在此，我们表明，在麻醉大鼠中，硬膜外超低频电流可逆地抑制接受感觉脊髓丘脑输入的丘脑神经元的激活。
在未经处理、患有神经病变和假手术的大鼠中，从丘脑神经元记录持续活动和诱发活动，目标是腹后外侧（VPL）核。
在32个接受腰段硬膜外超低频神经调节测试的神经元中，有25个（78%）对后肢感受野电刺激的反应降低。与对一系列刺激强度或仅对高强度刺激有反应的细胞相比，更有可能发现优先对低强度刺激有反应的细胞；并且低阈值反应比高阈值反应更有可能被超低频抑制。在未经处理动物的39个神经元中的17个（44%）中观察到的与后肢刺激无关的持续活动，在14个接受超低频测试的神经元中只有3个（21%）被腰段硬膜外超低频电流降低。相比之下，在具有明确神经病变损伤（脊髓神经结扎，SNL）的大鼠中，我们发现丘脑神经元中持续活动的发生率要高得多：55个神经元中的53个（96%）表现出与后肢刺激无关的放电。在该组中，超低频电流降低了29个接受测试的神经元中的19个（66%）的丘脑神经元放电率。在假手术动物中，丘脑神经元中这种活动的发生率以及超低频电流的影响与未经处理组无显著差异。
我们首先得出结论，超低频电流可以急性且可逆地中断感觉传入纤维与丘脑中继神经元之间的信号传递。其次，在神经病变损伤后的早期阶段，丘脑神经元的持续活动会显著增加。第三，与未经处理和假手术动物的正常活动相比，这种新型神经调节形式在该神经病变模型中优先减弱病理性丘脑活动。因此，本研究表明硬膜外超低频电流可以减少到达大脑的神经损伤相关异常活动。这些发现有助于推进对超低频神经调节镇痛作用可能机制的理解。
