大鼠內側丘腦投射路徑功能之磁振造影研究

Functional Mapping of Medial Thalamic Projections in Rat Using MRI

楊白峯(Pai-Feng Yang)

指導教授 ： 陳志宏 ； 嚴震東

國立臺灣大學/電機資訊學院/電機工程學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.01275

摘要

疼痛經常使人產生不愉快的感覺與情緒，同時往往影響正常的生理功能，而長期的疼痛更嚴重降低了生活的品質。因此對於疼痛產生的生理機制了解越多，對於未來疼痛治療的發展將會有很大的幫助。近幾年來，有兩種磁振造影相關技術被研發並應用於偵測特定腦區之間的神經網路連結及其功能，方法一為血氧濃度依賴對比(BOLD)與電刺激特定腦區並監測腦部的變化，方法二為錳離子影像增強磁振造影(MEMRI)。本論文將利用這兩項技術來研究大鼠的內側視丘(medial thalamus, MT)的投射路徑及疼痛訊息處理的功能。
第一部分的研究中發現刺激腹後視丘(ventroposterior nuclei, VP)會引發初級體感覺皮層(primary somatosensory cortex, S1)及紋狀體(striatum)之尾核被殼(caudate putamen, CPu)之BOLD反應上升，而刺激MT會引發扣帶皮質(cingulate cortex, CC)及CPu之BOLD反應上升，並且在比較兩者之電刺激引發的BOLD反應大小後，發現刺激MT比VP需要更強及更高頻率的電刺激，同時我們也發現電刺激這兩個腦區皆引起CPu的BOLD的反應下降(negative BOLD)。以c-Fos蛋白質標定細胞活性，發現電刺激MT會引起CC及CPu等腦區有大量的c-Fos反應，相反地電刺激VP後，在S1及CPu則無明顯的c-Fos反應。以上這些結果顯示MT與VP有著不同腦區連結與功能。
第二部分的研究，我們應用錳離子增強影像技術研究內側視丘投射路徑對傷害性刺激的反應。結果顯示對傷害性刺激產生反應的腦區主要位於CC，CPu，積核(nucleus accumbens)和retrosplenial cortex等腦區。施以嗎啡止痛後，CC，積核，及杏仁核對傷害刺激的反應明顯下降，顯示這些腦區與疼痛處理的功能有相關，而retrosplenial cortex的反應並無明顯改變，顯示此腦區在傷害訊息處理上有著不同的功能。
總結而言，本篇論文成功應用了磁振造影並且結合顱內電刺激及錳離子增強影像技術來偵測視丘投射路徑與其處理傷害性刺激訊息的功能，這對未來進行動物模型之疼痛研究將有很大助益。

關鍵字

磁振造影 ； 錳離子增強磁振造影 ； 疼痛 ； 視丘 ； 扣帶皮質

並列摘要

Pain is an unpleasant sensory and emotional experience and has significant influence on our normal function and quality of life. Therefore, it is important to understand pain mechanisms so that treatment of pain can be improved. In recent years, two MRI techniques are developed for mapping activation and connection patterns in specific brain circuits. The first one combines the blood oxygen level dependence (BOLD) responses and direct brain stimulation; and the other one is the manganese enhancement magnetic resonance imaging (MEMRI). In this dissertation, we used these methodologies to investigate the function and connection of the thalamic projections of the rat.
In the first experiment, we analyzed the BOLD activation patterns in the forebrain through direct electrical stimulation of the ventroposterior nuclei (VP) and the medial dorsal nuclei (MD) of the thalamus. A flexible MR-compatible polyimide-based microelectrode array was implanted in the VP or the MD in α-chloralose anesthetized rats. Electrical stimulation was used to activate the VP or MD. BOLD responses were found in many forebrain targets. The ipsilateral forelimb region of the primary somatosensory cortex (S1) was most prominently activated after VP stimulation. Strongest activations occurred at 3 Hz. The threshold intensity was low (50 μA) but maximal response was reached at 100 μA. In contrast, direct MD stimulation revealed major activated areas in the ipsilateral anterior cingulate cortex (ACC). The best frequency of stimulus was 9-12 Hz. Increasing either intensity or frequency of stimulation produced graded increase in BOLD responses. We also found negative BOLD responses in the CPu both with MD and VP stimulation. In addition, c-Fos positive neurons following VP or MD stimulation were totally distinct. VP stimulation elicited few c-Fos labeled neurons in the ipsilateral S1. In contrast, MD stimulation produced numerous c-Fos positive neurons in the ACC and other forebrain regions. The differential BOLD and c-Fos responses induced by VP versus MD stimulation may indicate a fundamental difference in the synaptic mechanism of the medial and the lateral thalamic pain pathways.
In the second experiment, we studied the nociceptive medial thalamus projection in rats by activity-dependent MEMRI. Rats under urethane and a-chloralose anesthesia were microinjected with manganese chloride (MnCl2, 120mmol/L, iontophoretically with a 5-μA current for 15 min) into the right medial thalamus, centered on MD. Innocuous (at 50-μA intensity and 0.2 ms pulse duration) or noxious (at 5-mA intensity and 2 ms pulse duration) electrical stimuli were applied through a pair of needles in the left forepaw pads once every 6 s for 5 h. Enhanced transport of Mn2+ were found in the ACC, mid-cingulate cortex, retrosplenial cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala in the noxious-stimulated group. Enhancements in the ACC, mid-cingulate cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala, but not the retrosplenial cortex, were attenuated by an intraperitoneal injection of morphine (5 mg/kg initially and 1 mg/kg/h infusion, intraperitoneal). These results indicate that a combination of MEMRI with activity-induced manganese-dependent contrast is useful for delineating functional connections in the pain pathway.
In summary, this dissertation has successfully demonstrated the potential of direct brain stimulation fMRI and MEMRI in the study of the connectivity and function of nociceptive processing in the brain.

並列關鍵字

fMRI ； BOLD ； c-Fos ； Cingulate cortex ； Medial dorsal nucleus ； Pain ； Rat ； Thalamus

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