臺灣博碩士論文加值系統

原發性之突發感音神經性聽覺損失(idiopathic sudden sensorineural hearing loss, ISSNHL；以下簡稱為突發性聽覺損失)，其發生率約為4~50人/十萬人/年，隨年齡而增加。突發性聽覺損失的致病機轉、神經缺損定位(localization of neural deficits)，及大腦聽覺皮質層之功能性調節(functional modulation of auditory cortex)迄今仍不清楚。由於突發性聽覺損失病患中，大約有三分之一其聽力在治療後能完全恢復，可以觀察到發病時以及聽覺功能恢復後，病患聽覺傳導路徑(auditory pathway)中，聽覺神經可塑性(auditory neuroplasticity)變化的過程，因此可說是各種感音神經性聽覺損失中，研究聽覺神經可塑性的極佳對象。本研究主題為探討突發性聽覺損失中樞聽覺神經可塑性之表現，研究涵蓋下列子題︰

突發性聽覺損失晚期潛時值聽性誘發磁場(long-latency auditory evoked fields; LLAEFs, N100m)之健側優勢(healthy-side dominance)
首先探討的是：急性期突發性聽覺損失病患中樞聽覺傳導路徑之聽覺神經可塑性變化型式。過去的學者曾嘗試以腦磁圖(Magnetoencephalogram; MEG)與功能性磁振造影(functional Magnetic Resonance Imaging; fMRI)等檢查，來探究突發性聽覺損失病患大腦聽覺皮質層之功能性變化，並發現中樞聽覺傳導路徑的確具有動態可塑性(dynamical plasticity)的現象，但對於急性期突發性聽覺損失病患中樞聽覺傳導路徑之聽覺神經可塑性變化型式，則未有具體結論。因為前述的聽性大腦皮質反應(auditory cortical response)研究，其受試者多為單側之重度聽覺損失病患，且其病程多已進入慢性期；當刺激音經由患側耳傳入時，聽性大腦皮質反應往往由於重度聽覺損失而無法被誘發，因此僅能侷限於觀察聽覺刺激經由健側耳所誘發之聽性大腦皮質反應。本研究則慎選急性期單側之輕度或中度突發性聽覺損失患者，並使用306頻道全頭式腦磁波探測儀(306 channel whole-head neuromagnetometer)，在具有磁場遮蔽(magnetically shielded)效應之檢查室中，來觀察其晚期潛時值聽性誘發磁場(long-latency auditory evoked fields; LLAEFs, N100m)。如此，則不論刺激音是由健側耳或患側耳傳入，都能夠很清楚地被腦磁圖偵測到。結果，在聽力正常之對照組(n=9)，不論從左側或右側耳給予刺激，對側大腦聽覺皮質層所測得之N100m電偶極矩(dipole)強度，都比同側所測得者為強(18 measurements; p=0.008)。而在病患組(n=9)，不論從健側或患側耳給予刺激，與健側耳同側之大腦聽覺皮質層所測得之N100m電偶極矩強度，都比另一側所測得者為強(18 measurements; p<0.001)。實驗結果顯示，此類患者確有特殊的晚期潛時值聽性誘發磁場反應型式，可稱為健側優勢(healthy-side dominance)：刺激患側耳時，聽性誘發磁場與正常人一樣，依舊保留對側優勢；而刺激健側耳時，則發生了聽覺神經可塑性變化，呈現同側優勢(ipsilateral dominance)。

突發性聽覺損失中期潛時值聽性誘發磁場(middle-latency AEFs; MLAEFs, P50m)之健側優勢
欲明瞭健側優勢之生理意義，必須先知道這種在大腦聽覺皮質層所觀察到的聽覺神經可塑性變化，到底源自聽覺傳導路徑中的哪個階層。接續前述研究，本實驗透過腦磁圖優越之臻毫秒高時間解析度，同步量測晚期及中期潛時值聽性誘發磁場(middle-latency AEFs; MLAEFs, P50m)，來分析健側優勢之時序變化。病患組包括16位左側(n=8)或右側急性期突發性聽覺損失患者，其中8位為男性；對照組則為16位聽力正常之成人，其中8位為男性。如前述研究，本實驗以1000Hz之單耳純音(monaural pure tone)為刺激音，並使用Wilcoxon signed rank test (threshold at p < 0.05)，來計算組內(within-group)於100及50毫秒左右，在兩側大腦聽覺皮質層所測得之N100m及P50m電偶極矩的強度與潛時值之差異。在對照組，不論從左側或右側耳給予刺激，對側大腦之聽覺皮質層所測得之P50m電偶極矩強度，都比同側所測得者為強(32 measurements; p<0.001)。而在病患組，不論從健側或患側耳給予刺激，與健側耳同側之大腦聽覺皮質層所測得之P50m電偶極矩強度，都比另一側所測得者為強(32 measurements; p<0.001)。N100m之檢測結果與P50m類似。實驗結果可以確認，急性期單側之突發性聽覺損失患者，中樞聽覺傳導路徑之聽覺神經可塑性變化，不僅發生在晚期潛時值聽性誘發磁場，也發生在中期潛時值聽性誘發磁場。可見健側優勢之現象，係在聲音訊息傳達到大腦聽覺皮質層後不久，即已發生。

突發性聽覺損失中期及晚期潛時值聽性誘發磁場健側優勢之機轉
欲明瞭健側優勢之機轉，必須先知道這種聽覺神經可塑性變化，相對於聽力正常之成人而言，到底係因健側大腦聽覺皮質層之反應較強，抑或患側大腦聽覺皮質層之反應較弱，甚或同時發生所致。本研究以1000Hz之單耳純音為刺激音，利用腦磁圖，同步量測晚期及中期潛時值聽性誘發磁場，並使用變異數分析(ANOVA) (以Games-Howell為事後檢定；threshold at p < 0.05)，來分析組間(between-group)於100及50毫秒左右，在兩側大腦聽覺皮質層所測得之N100m及P50m電偶極矩的強度與潛時值之差異。病患組包括16位左側(n=8)或右側早期突發性聽覺損失患者，其中8位為男性；對照組則為16位聽力正常之成人，其中8位為男性。組間之比較顯示，從患者之健側耳給予刺激時，P50m電偶極矩之強度係呈現對側大腦明顯較對照組為弱(p=0.013)，而同側大腦明顯較對照組為強(p<0.001)之現象。N100m之檢測結果與P50m類似。因此，突發性聽覺損失患者，中期及晚期潛時值聽性誘發磁場健側優勢之機轉，係與從病患之健側耳(而非患側耳)給予刺激時，同時發生了聽性誘發磁場在對側(患側)受到抑制(contralateral inhibition)，以及同側(健側)更進一步增強(enhanced ipsilateral excitation)之現象有關。

突發性聽覺損失晚期潛時值聽性誘發磁場之長期趨勢
為明瞭健側優勢可能的臨床應用價值，作者針對急性期單側之突發性聽覺損失患者(n=16)，進行長期追蹤的縱向研究(longitudinal studies)，以便確認神經磁場反應(neuromagnetic responses)之變化與距離病發時間，以及聽覺功能損壞之嚴重度等方面之間的關係。作者以側化指數(laterality index)來探究突發性聽覺損失患者，發病後會產生多大程度之聽性大腦皮質反應改變，並藉以描述健側優勢之聽覺神經可塑性變化型式，隨病程而產生的變化。研究之目的在於驗證此種神經磁場反應型式(健側優勢)，是否可作為臨床上有效的預後(prognosis)指標；亦即，此種優勢化表現(dominance expression)，是否會隨著聽覺功能之恢復而有所變化。實驗結果顯示，側化指數可作為聽覺神經可塑性變化之良好指標，具有預後參考價值。

結論
本研究之主要結論包括：
1.對於急性期單側之突發性聽覺損失病患，不論從健側或患側耳給予聲音刺激，聲音訊息主要都是由與健側耳同側之大腦聽覺皮質層來處理。
2.這種特殊的聽覺神經可塑性變化型式，係在聲音訊息幾乎剛傳遞到大腦聽覺皮質層進行處理時，即已呈現。
3.而(大腦聽覺皮質層)健側優勢之機轉，則為「與健側耳同側之大腦聽覺皮質層對聲音產生較強反應，另一側則產生較弱之反應」。
4.側化指數可作為聽覺神經可塑性變化之良好指標，具有預後參考價值。

健側優勢之生理意義，推測可能與大腦半球間(inter-hemispheric)互相抑制之作用失調，或者與大腦聽覺皮質層之神經可塑性變化因單側聽覺損失被啟動，以補償未能最佳化的雙耳交互作用(compensation for loss of optimal binaural interaction)有關。由於中期潛時值聽性誘發磁場含有來自大腦皮質下(subcortical)神經核的影響，因此這種聽覺神經可塑性變化在聽覺傳導路徑中的最初起源，推測可能在大腦皮質下神經核即已發生。過去的動物實驗已證明，內耳損傷可導致中樞聽覺傳導路徑之抑制性神經傳導素(neurotransmitter)分泌失衡，以致於大腦聽覺神經元及其接受器(receptor)等突觸活性(synaptic activity)產生了功能或結構上的重組。由於本研究所觀察到的聽覺神經可塑性變化，並不見於刺激患側耳之實驗狀況，反而是在刺激健側耳時發生，因此，這個發現對於內耳損傷所引起的聽覺神經可塑性變化之機轉，提供了具參考性的思考方向：可能係因患側內耳釋放出某些神經傳導素，經由耳蝸後聽覺傳導路徑傳遞至對側，造成無病灶之健側聽覺傳導路徑，也發生了聽覺神經可塑性變化。這種聽覺神經可塑性變化，可提供患者迅速適應聽覺環境改變的微調能力，有助於聲音處理歷程的最佳化。這些推測仍待繼續探討。

Magnetoencephalography (MEG) and functional Magnetic Resonance Imaging (fMRI) studies have verified a contralateral dominance of auditory evoked response by monaural stimulation on normal subjects. Though previous brain imaging and mapping studies have reported findings indicating functional reorganization in the central auditory pathways of patients with profound unilateral hearing loss, localization of neural deficits and functional modulation of auditory cortex by idiopathic sudden sensorineural hearing loss (ISSNHL) remain unclear. To address a series of questions on the pathophysiology and the mechanisms of central plasticity of ISSNHL, we have performed a 3-study plan for the past years in the Institute to resolve both scientific questions and methodological implementations. We will continue further studies to unravel auditory neuroplasticity in the human brain on patients with acute unilateral ISSNHL.

In the first study, we reported for the first time, using a whole-head neuromagnetometer with monaural stimulation of both intact and affected ears, a pattern of “healthy-side dominance” for long-latency auditory evoked fields (LLAEFs; N100m) in adult patients during the early stage of unilateral ISSNHL, while a pattern of contralateral dominance is verified in controls. Of note, LLAEFs provide a non-invasive and objective measure of human CNS activity. Contralateral dominance is preserved on affected ear stimulation but lost on healthy ear stimulation in ISSNHL patients. Our work is the first MEG study ever reporting such finding and is corroborated by a recent fMRI study in which evidence of healthy-side dominance can be noted in patients with unilateral deafness. Though the actual mechanisms are currently unknown, the pattern of “healthy side dominance” is suspected to be related to the reduction of interhemispheric inhibition or to the neuroplasticity as a compensation for loss of optimal binaural interaction. Besides, this functional plasticity can be coupled with structural changes since damage of the peripheral organ has been demonstrated to induce cellular changes in the central auditory pathway.

In the second study, we confirmed that functional reorganization of central auditory pathway in patients with acute unilateral ISSNHL occurs not only in the LLAEFs, but also in the middle-latency auditory evoked fields (MLAEFs; P50m), i.e., within first few milliseconds as transient sounds arrive at the auditory cortex, with. However, the question remained on the level where the reorganization begins. On the other hand, our MEG findings seem to correlate well with indices of auditory plasticity at molecular level, for example, changes of synaptic activity (including neurotransmitters and/or receptors) in central auditory pathway. These changes could provide fine tuning for an optimization of processing requirements and to react/adapt to changes in input in conditions such as our patients encountered. Continuous work with similar paradigm and/or different functional mapping modalities should be able to provide insight into the underlying mechanism of healthy-side dominance, into how the central auditory pathway might respond to loss and restoration of afferent activity, and thus into the prediction of the prognosis in ISSNHL patients.

In the third study, we performed a series of longitudinal MEG tests on patients with unilateral ISSNHL to characterize the neuroplastic changes and functional impairment as measured by various clinical standard assessments, e.g. pure tone audiometry (PTA), auditory brainstem responses (ABRs), and otoacoustic emissions (OAEs) during the follow-ups. The goals were to investigate the extent to which cortical activation changes following acute unilateral ISSNHL in terms of contralaterality index and to describe the time course of the changes of the “healthy-side dominance” cortical activation pattern. Changes in cortical activity associated with unilateral ISSNHL were assessed by measuring the LLAEFs. Our findings revealed that laterality index is a good indicator of auditory plasticity, and may be of prognostic relevance.

In the future, we will continue elucidating the pathophysiology of central auditory pathway in patients with acute unilateral ISSNHL by means of cross-modality approaches including MEG, fMRI, electroencephalography (EEG), and positron emission topography (PET). The methods implemented for this proposal are expected to become non-invasive new tools for clinical diagnosis. Both the technical implementations and scientific questions probed mandate sophisticated setup and orchestration among several disciplines. We believe that our innovative studies will give rise to a profound understanding of central mechanisms of ISSNHL.

連副院長序…………………………………………………………………………...4
致謝…………………………………………………………………………………...6
中文摘要……………………………………………………………………………...8
突發性聽覺損失晚期潛時值聽性誘發磁場之健側優勢……………………...8
突發性聽覺損失中期潛時值聽性誘發磁場之健側優勢……………………...9
突發性聽覺損失中期及晚期潛時值聽性誘發磁場健側優勢之機轉……….10
突發性聽覺損失晚期潛時值聽性誘發磁場之長期趨勢…………………….11
結論…………………………………………………………………………….11
Abstract …………………………………………………………………………….13
縮寫………………………………………………………………………………….15
背景………………………………………………………………………………….18
突發性聽覺損失大腦聽覺皮質層之聽覺神經可塑性變化………………….20
突發性聽覺損失大腦聽覺皮質層聽覺神經可塑性變化之起源…………….22
突發性聽覺損失大腦聽覺皮質層聽覺神經可塑性變化之長期趨勢……….24
材料與方法………………………………………………………………………….25
實驗一………………………………………………………………………….26
實驗二………………………………………………………………………….29
實驗三………………………………………………………………………….32
結果………………………………………………………………………………….35
實驗一………………………………………………………………………….36
實驗二………………………………………………………………………….38
實驗三………………………………………………………………………….43
討論………………………………………………………………………………….51
實驗一………………………………………………………………………….52
實驗二………………………………………………………………………….55
實驗三………………………………………………………………………….61
結論與展望………………………………………………………………………….65
圖表………………………………………………………………………………….68
參考文獻…………………………………………………………………………….91
相關會議及獎項…………………………………………………………………...101
相關著作…………………………………………………………………………...103
Health-Side Dominance of Cortical Neuromagnetic Responses Evoked by Monaural Stimulation in Patients with Sudden Hearing Loss. Ann Neurol 2003; 53: 810-815 ………………………………………………………………...104
Healthy-Side Dominance of Middle- and Long-Latency Neuromagnetic Fields in Idiopathic Sudden Sensorineural Hearing Loss. Eur J Neurosci 2006, in press
………………………………………………………………………………..110
Reversal of Healthy Side Dominance of Neuromagnetic Responses in Sudden Hearing Loss after Functional Recovery: Laterality Index as an Index of Prognosis. (in preparation) ………………………………………………...120

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