透過多種功能性磁振造影方法搜尋大鼠於坐骨神經性疼痛發展過程中前腦活動及功能性連結之可塑性變化

Abstract

疼痛是一種由實質或潛在組織傷害所致的不適感與負面情緒，而過度強烈且持續的疼痛損害我們的生活品質。全世界約有百分之二十的人口受慢性疼痛所苦。相較於急性疼痛的患者，慢性疼痛患者鮮少獲得有效治療。在各式各樣的慢性疼痛中，神經病變性疼痛尤為難以治療。神經病變性疼痛肇因於周邊神經受損失能，並常常發展成慢性疼痛。已知周邊神經受損會誘發異位放電，我們猜想周邊神經受損亦導致前腦部分腦區持續活化，並使這些腦區最終發展出與慢性疼痛症狀相關的可塑性改變。本篇論文致力於利用多種磁振造影和電生理方法，在大鼠坐骨神經受損誘發神經病變性疼痛的過程中，偵測前述假設的前腦持續活化和可塑性改變。 首先，我們發展出利用右旋美托嘧啶作為鎮靜劑的血氧濃度依存功能性磁振造影來長期監測特定視丘皮質迴路突觸連結強度的實驗方法。我們使用一對鎢絲電極（其僅會在電極周遭的影像造成尚可接受的訊號干擾）來電刺激腹後側視丘-初級感覺皮質迴路，並在初級感覺皮質觀察到穩定的刺激頻率對血氧濃度反應曲線和刺激強度對血氧濃度反應曲線。這些位於初級感覺皮質的血氧濃度反應在為期一週的間隔中皆表現出穩定的反應強度、體積、位置。 在論文的第二部分，我們結合了血氧濃度依存功能性磁振造影和錳離子增益磁振造影，偵測神經病變性疼痛三個不同發展階段中前腦的活化狀態。包含使用血氧濃度依存功能性磁振造影偵測坐骨神經受損當下的前腦活動，以及使用錳離子增益磁振造影偵測前腦於坐骨神經受損後第一天和第八天的基礎活動。我們發現雙側的島葉皮質和損傷對側的初級感覺皮質在坐骨神經受損後立即產生持續的活化，這些腦區而後長期地活動增加，且與其他腦區發生異常功能性連結。透過電生理方法和利用血氧濃度依存功能性磁振造影偵測初級感覺皮質對腹後側視丘電刺激的反應，我們發現在坐骨神經受損後，損傷下游的視丘-初級感覺皮質迴路以及其鄰近完好的視丘-初級感覺皮質迴路表現出截然不同的可塑性變化。與此相對，對周邊刺激反應範圍較大且不專一的吻端前島葉皮質與前扣帶迴皮質，其與對應視丘的連結強度則在坐骨神經受損後一致地增強。 藉由結合多種方法切入，我們不但提供了坐骨神經受損後，前腦可塑性變化的整合性研究結果，並示範了如何將不同的功能性磁振造影法截長補短以運用於大腦可塑性研究。

Pain is an unpleasant sensory and emotional experiences associated with actual or potential tissue damage, excessive and chronic pain harmful to the quality of life. Chronic pain is a major health problem which affects up to 20% of the general population. Although acute pain patients can be properly managed, most of the chronic pain patients fail to achieve adequate pain relief. Among the most difficult ones are the neuropathic pain patients. Neuropathic pain is initiated by a primary lesion or dysfunction in the nervous system, and often causes chronic pain. It had been known that peripheral nerve damage induced early onset of ectopic discharge in injured nerve fibers. We hypothesized that peripheral nerve injury also induces sustained activation in the forebrain, and these brain areas eventually develop plasticity changes involved in chronic neuropathic pain. In this dissertation, we aimed to identify the sustained activation and the plasticity changes of forebrain during the development of Spared Nerve Injury (SNI) induced neuropathic pain via multiple magnetic resonance imaging (MRI) and electrophysiological recording approaches. First, we aim to longitudinally monitor the synaptic connectivity of the specific thalamocortical pathway via dexmedetomidine-based blood oxygen level dependent functional MRI (BOLD-fMRI) protocol. In this study, a pairs of tungsten electrodes, which caused acceptable susceptibility artifact limited around the electrodes, were used to target the ventroposterior thalamus – primary somatosensory (VP-S1) pathway. We discovered reproducible frequency- and amplitude-dependent BOLD responses in the ipsilateral S1. The S1 BOLD responses during the 2 sessions (one week apart) were conserved in response amplitude, area size, and location.

In the second part, we combined the BOLD-fMRI and manganese-enhanced MRI (MEMRI) to monitor the brain activation during three different neuropathic pain development stages, including the brain activation at the moment of nerve injury detected using BOLD-fMRI, and the brain activity during the 1st and the 8th day using MEMRI. We observed tonic activation in bilateral insular cortices and contralateral S1 immediately after the SNI, and these areas established long-term abnormal functional connectivities. By using the electrophysiological and DBS-fMRI approach, we found the primary injured VP-S1 pathway and surrounding VP-S1 pathway established different thalamocortical plasticity after the SNI, whereas the rostral anterior insular and the anterior cingulate cortex, which have large and diffusive receptive field, showed consistent enhanced thalamocortical connection after the SNI.

By combination of multiple approaches, we not only provided an integrated result of functional brain changes after peripheral neuropathy, but also demonstrated an example framework to study the brain plasticity by combining multiple fMRI methods that complement each other.