周邊與中樞神經系統於正常人與神經病變中處理熱覺與痛覺機轉之研究

Abstract

體感覺(somatosensory)異常尤其疼痛是病人最常到醫院尋求幫助的理由之一，許多疼痛症候群很難以藥物治療改善，尤其是神經痛。這些疼痛症候群不僅影響到身心健康，也是社會經濟的一大負擔。但是，由於周邊與中樞神經系統對於體感覺刺激的處理機轉尚未完全清楚，導致開發新治療的進度緩慢。本研究希望藉由皮膚切片及定量表皮內神經纖維密度與功能性磁振造影分別於周邊與中樞神經系統中釐清熱覺與痛覺的運作機制。 第一部分的研究目標旨在釐清於周邊神經系統當中，表皮內感覺神經對體感覺扮演的角色，並了解紅斑性狼瘡(systemic lupus erythematosus)病患皮膚內神經退化之情形與其臨床意義。我們募集了四十五位符合診斷條件之紅斑性狼瘡病患(四位為男性，四十一位為女性，平均年齡38.4 ± 13.6歲)，評估其下肢遠端的表皮內神經纖維密度，將其與皮膚病理、免疫學指標、心理感覺及電生理檢查結果做分析。和年齡與性別與病人相配對之正常人相比，紅斑性狼瘡病患表皮內神經纖維密度明顯降低(3.08 ± 2.17 versus 11.27 ± 3.96 fibres/mm, P < 0.0001)，所有病患中有三十八位病患(百分之八十二點二)具有異常之表皮內神經纖維密度。整體而言，共有十一位病患(百分之二十四點四)的皮膚具有明確血管炎(definite vasculitis)，皮膚內血管炎的嚴重度及範圍與表皮內神經纖維密度的減少有很強的相關性。與疾病活性為非活耀(quiescent)者相比，紅斑性狼瘡疾病活性為活耀(active)者其下肢表皮內神經纖維密度較少(1.86 ± 1.37 versus 4.15 ± 2.20 fibres/mm, P = 0.0002)。經由線性迴歸分析後發現，表皮內神經纖維密度不僅與紅斑性狼瘡疾病活性指標SLEDAI呈負相關(r = 0.527, P = 0.0002)，亦與接受皮膚切片前二年內紅斑性狼瘡急性復發(flare-up)累積次數呈負相關(r = 0.616, P = 0.0014)。臨床上，不僅感覺神經病變的患者其表皮內神經纖維密度有減少，具有中樞神經精神症候群(neuropsychiatric syndrome)表現之病患其表皮內神經纖維密度亦顯著降低。與正常人比起來，紅斑性狼瘡病患的腳趾對熱覺的閥值明顯較高(P = 0.003)，表皮內神經纖維密度亦與熱覺的閥值呈相關性(P = 0.032)。 在第一部份研究的結論裡，我們證明了表皮內神經纖維密度反映了溫覺與痛覺的表現，顯示皮膚切片與定量表皮內神經纖維的密度足以成為研究周邊神經關於溫覺與痛覺的客觀工具。此外，皮膚內血管炎以及紅斑性狼瘡疾病活性影響表皮內的神經產生退化，伴隨著熱覺閥值的上升，是為紅斑性狼瘡感覺神經病變的主要表現。 第二部分的研究是希望了解中樞神經系統中，腦部對熱覺與痛覺的反應模式。我們募集了十二位慣用右手，年齡介於二十五至六十七歲（平均四十一歲）之正常人（六男六女），在右腳腳背上以接觸性熱刺激施予38 °C無痛熱刺激及44 °C痛刺激，利用功能性磁振造影探索腦部反應模式。從分析腦部集體活化圖(group activation maps)的過程中，我們可以將腦部對熱與痛刺激反應之空間模式總結成以下三種:(1)只在無痛熱刺激下活化者: 下頂小葉(inferior parietal lobule)；(2)只在痛刺激下活化者: 初級體感覺皮質(primary somatosensory cortex)、次級體感覺皮質(secondary somatosensory cortex)、後腦島(posterior insular cortex)、前運動區(premotor area)；(3)熱與痛刺激下皆活化者:中額腦迴(middle frontal gyrus)、下額腦迴(inferior frontal gyrus)、前腦島(anterior insular cortex)、小腦(cerebellum)、上額腦迴(superior frontal gyrus)、視丘(thalamus)、前扣帶皮質(anterior cingulate cortex)、豆狀核(lentiform nucleus)，以及刺激對側的運動輔助區(supplementary motor area)與中腦(midbrain)。在目標區域(regions of interest)進行的時序分析發現，在刺激的整個過程中，下頂小葉只在無痛熱刺激下才被活化，而次級體感覺皮質、後腦島與前運動區則只有當刺激為疼痛時才會被活化。幾處腦部集體活化圖裡歸類為熱與痛刺激下皆活化的腦區，包括視丘、前扣帶皮質、豆狀核與下額腦迴，顯然在無痛熱刺激與痛刺激的不同時期有不同的活化反應。而腦部集體活化圖分析裡歸類為只在痛刺激下活化之初級體感覺皮質事實上亦參與了無痛熱刺激早期的知覺。此外，兩側下頂小葉在38 °C無痛熱刺激下所產生之腦部血氧濃度相依對比資料(blood oxygen level-dependent)訊號與受試者評估之熱覺程度呈正相關，而初級體感覺皮質與次級體感覺皮質在44 °C痛刺激下所產生之腦部血氧濃度相依對比資料訊號強度則與痛覺程度呈正相關。這些結果顯示我們的腦部之所以能區分熱覺與痛覺的不同，決定於活化腦區的不同、腦區活化的程度以及刺激的不同階段這些因素。

One of the most popular reasons that people come to the hospital for help is the symptoms caused by abnormal somatosensation, particularly pain. Many pain syndromes, particularly neuropathic pain, are usually refractory to medical treatment, which affect the psychophysical well-beings and become a burden on social economics. However, the incomplete understanding about the peripheral and central mechanisms of somatosensory processing impedes the development of new therapeutic strategies. By applying the punch skin biopsy technique with quantification of the intraepidermal nerve fibre (IENF) density to investigate the peripheral nervous system and functional MRI in the central nervous system (CNS), we aim to clarify the mechanisms of thermal and pain processing in healthy human and neuropathy. The purpose in the first part of our study is (1) to investigate the role of the IENF in the processing of somatosensation in the peripheral nervous system, and (2) to understand the clinical significance and mechanisms of cutaneous denervation in systemic lupus erythematosus (SLE). We assessed IENF density of the distal leg in 45 SLE patients (4 males and 41 females, aged 38.4 ± 13.6 years) and analysed its correlations with pathology, lupus activity, sensory thresholds and electrophysiological parameters. Compared with age- and gender-matched control subjects, SLE patients had lower IENF densities (3.08 ± 2.17 versus 11.27 ± 3.96 fibres/mm, P < 0.0001); IENF densities were reduced in 38 patients (82.2%). Pathologically, 11 patients (24.4%) were found to have definite cutaneous vasculitis; the severity and extent of cutaneous vasculitis were correlated with IENF densities. Patients with active lupus had even lower IENF densities than those with quiescent lupus (1.86 ± 1.37 versus 4.15 ± 2.20 fibres/mm, P = 0.0002). By linear regression analysis, IENF densities were negatively correlated with the SLE disease activity index (r = 0.527, P = 0.0002) and cumulative episodes of lupus flare-up within 2 years before the skin biopsy(r = 0.616, P = 0.0014). Clinically, skin denervation was present not only in the patients with sensory neuropathy but also in the patients with neuropsychiatric syndrome involving the CNS. SLE patients had significantly elevated warm threshold temperatures (P = 0.003) and reduced cold threshold temperatures (P = 0.048); elevated warm threshold temperatures were associated with the reduced IENF densities (P = 0.032). Taken together, we provide several lines of evidence that IENF reflects thermal and pain sensation, and skin biopsy with quantification of the IENF density was proved as a objective tool to evaluate temperature sensation in the peripheral nervous system. Cutaneous vasculitis and lupus activities underlie skin denervation with associated elevation of thermal thresholds as a major manifestation of sensory nerve injury in SLE. The aim in the second part of our study is to understand the response patterns to innocuous heat (IH) and noxious heat (NH) in the brain. Whether IH-exclusive brain regions exist and whether patterns of cerebral responses to IH and NH stimulations are similar remain elusive. We hypothesized that distinct and shared cerebral networks were evoked by each type of stimulus. Twelve normal subjects participated in a functional MRI study with rapidly ramped (up to 20 °C/sec) IH (38 °C) and NH (44 °C) applied to the right foot. Group activation maps demonstrated 3 patterns of cerebral activation: (1) IH-responsive only in the inferior parietal lobule (IPL); (2) NH-responsive only in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), posterior insular cortex (IC), and premotor area (PMA); and (3) both IH- and NH-responsive in the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), anterior IC, cerebellum, superior frontal gyrus, supplementary motor area, thalamus, anterior cingulate cortex (ACC), lentiform nucleus (LN), and midbrain. According to the temporal analysis of regions of interest, the IPL exclusively responded to IH, and the S2, posterior IC, and PMA were exclusively activated by NH throughout the entire period of stimulation. The IFG, thalamus, ACC, and LN responded differently during different phases of IH versus NH stimulation, and the NH-responsive-only S1 responded transiently during the early phase of IH stimulation. BOLD signals in bilateral IPLs were specifically correlated with the ratings of IH sensation, while responses in the contralateral S1 and S2 were correlated with pain intensity. In conclusion, these results suggest that unique brain areas process IH and NH differently in terms of activation location, response intensity, and phase of stimulation.