Systematic characterization of spinal cord stimulation effects on dorsal horn populations

脊髓刺激对背角群体影响的系统表征

• 批准号: 10558269
• 负责人: Andrei D Sdrulla
• 金额: $ 169.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558269
• 关键词: Afferent Pathways; Algorithms; Biological; Biology; Biophysics; C Fiber; Calcium; Chronic; Clinical; Data; Detection; Development; Devices; Distal; Electrodes; Electrophysiology (science); Fiber; Foundations; Frequencies; Genetically Engineered Mouse; Glutamates; Goals; Growth; Health; Image; Imaging Techniques; Implant; In Vitro; Knowledge; Label; Limb structure; Longevity; Lumbar spinal cord structure; Marketing; Mediating; Methods; Microscopy; Mission; Molecular; Morphologic artifacts; Mus; Neurons; Neurostimulation procedures of spinal cord tissue; Nociception; Noise; Outcome; Output; Pathway interactions; Patient Care; Patients; Peripheral; Persons; Physiologic pulse; Physiological; Population; Posterior Horn Cells; Preparation; Public Health; Research; Sampling; Site; Spinal Cord; Stimulus; Techniques; Technology; Testing; Transgenic Mice; United States National Institutes of Health; Width; calcium indicator; chronic back pain; chronic painful condition; clinical effect; clinically relevant; control theory; design; dorsal column; dorsal horn; electric field; experience; experimental study; human disease; improved; in vivo; inhibitory neuron; innovation; mouse model; multiphoton microscopy; neural stimulation; neuronal circuitry; neuroregulation; next generation; novel; pain relief; personalized medicine; prescription opioid; recruit; response; treatment program

There is a substantial need to understand the fundamental biological mechanisms of neuromodulation therapies in order to improve clinical delivery and outcomes (RFA-NS-20-006). Intractable chronic pain of the back and limbs continues to be challenging to treat clinically, and spinal cord stimulation (SCS) devices have experienced tremendous market growth despite a lack of an accepted mechanistic basis. There is minimal knowledge of how SCS engages dorsal horn circuits, primarily due to technical limitations associated with traditional electrophysiological recordings, such as stimulation-induced electrical noise artifacts and low sampling power. Multiphoton microscopy provides a novel and powerful approach to characterize the dorsal horn circuits modulated by SCS in transgenic mice genetically engineered to express calcium indicators in molecularly defined populations. An implantable miniature bipolar SCS electrode will be utilized to study the entire spectrum of clinically-relevant stimulation parameters on superficial dorsal horn populations. A wide range of frequencies, duty cycles, and waveforms will be investigated. Preliminary experiments demonstrated that SCS at 50 Hz drives sustained firing preferentially in GABAergic populations. We plan to systematically characterize the effects of stimulation parameters on GABAergic (Aim 1) and glutamatergic (Aim 2) populations. Neuronal networks distal and proximal to the SCS electrode will be examined, allowing the quantification of dorsal column and electrical field mediated effects, respectively. Nociceptive-range stimulation of afferent pathways will be combined with SCS to characterize responses in labeled output projection neurons, both in vitro and in intact mice implanted with a chronic imaging window (Aim 3). The Gate Control Theory suggested that activation of dorsal columns activates inhibitory neurons residing in laming II; this notion will be directly tested in Aim 1 using imaging techniques with superior sampling power and impervious to stimulation artifacts. This approach will provide an unprecedented understanding of the impact of SCS parameters, including energy delivery, on the activity of dorsal horn neurons over prolonged periods. This project's central goals are closely aligned with the RFA by proposing experiments to characterize cellular responses to neurostimulation in a relevant mouse model, with clear translational implications. Findings from these studies are expected to lay the foundation for the design and refinement of next-generation neuromodulation devices and substantially impact patient care.

为了改善临床治疗和结果，迫切需要了解神经调节疗法的基本生物学机制 (RFA-NS-20-006)。背部和四肢的顽固性慢性疼痛在临床上治疗仍然具有挑战性，尽管缺乏公认的机制基础，脊髓刺激（SCS）设备却经历了巨大的市场增长。人们对 SCS 如何参与背角电路知之甚少，这主要是由于与传统电生理记录相关的技术限制，例如刺激引起的电噪声伪影和低采样功率。多光子显微镜提供了一种新颖而强大的方法来表征转基因小鼠中受 SCS 调节的背角电路，该转基因小鼠经过基因工程改造，可在分子定义的群体中表达钙指示剂。植入式微型双极 SCS 电极将用于研究浅表背角群体的整个临床相关刺激参数。将研究各种频率、占空比和波形。初步实验表明，50 Hz 的 SCS 优先驱动 GABA 能群体的持续放电。我们计划系统地表征刺激参数对 GABA 能（目标 1）和谷氨酸能（目标 2）群体的影响。将检查 SCS 电极远端和近端的神经元网络，从而分别量化背柱和电场介导的效应。传入通路的伤害感受范围刺激将与 SCS 相结合，以表征标记输出投射神经元的反应，无论是在体外还是在植入慢性成像窗口的完整小鼠中（目标 3）。门控制理论表明，背柱的激活会激活位于 Laming II 中的抑制性神经元；这一概念将在目标 1 中使用具有卓越采样能力且不受刺激伪影影响的成像技术进行直接测试。这种方法将提供对 SCS 参数（包括能量传递）对背角神经元长期活动影响的前所未有的了解。该项目的中心目标与 RFA 密切相关，通过提出实验来表征相关小鼠模型中细胞对神经刺激的反应，并具有明确的转化意义。这些研究的结果预计将为下一代神经调节设备的设计和完善奠定基础，并对患者护理产生重大影响。