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; 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.

为了改善临床分娩和结果（RFA-NS-20-006），需要了解神经调节疗法的基本生物学机制。背部和四肢的顽固性慢性疼痛在临床上仍然具有挑战性，尽管缺乏公认的机械基础，但脊髓刺激（SCS）设备仍经历了巨大的市场增长。关于SC如何参与背喇叭电路的知识最少，这主要是由于与传统电生理记录有关的技术限制，例如刺激引起的电噪声伪像和低采样能力。多光子显微镜提供了一种新颖而有力的方法，可以表征转基因小鼠中SCS调制的背喇叭回路，该方法是经过基因工程的，以表达分子定义的种群中的钙指标。可植入的微型双极SC电极将用于研究浅表背角种群上临床上相关的刺激参数的整个光谱。将研究各种频率，占空比和波形。初步实验表明，在50 Hz处的SC驱动器在GABA能量中优先发射。我们计划系统地表征刺激参数对GABA能（AIM 1）和谷氨酸能（AIM 2）种群的影响。将检查神经元网络远端和SCS电极近端，分别允许对背侧柱和电场介导的效应进行定量。对传入途径的伤害性范围刺激将与SC相结合，以表征标记的输出投影神经元的响应，无论是在体外和植入慢性成像窗口的完整小鼠中（AIM 3）。栅极控制理论表明，背柱的激活激活了laming II中的抑制性神经元。该概念将使用具有出色的采样能力的成像技术直接在AIM 1中进行测试，并且不受刺激伪像。这种方法将对SCS参数的影响（包括能量输送）对长时间的背角神经元活性（包括能量输送）的影响提供前所未有的理解。通过提出实验来表征相关小鼠模型中的细胞对神经刺激的反应，并具有明显的翻译含义，该项目的中心目标与RFA紧密一致。这些研究的发现预计将奠定下一代神经调节装置的设计和完善基础，并显着影响患者护理。