JP7278948B2 - 神経調節のための技術 - Google Patents
神経調節のための技術 Download PDFInfo
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Description
図7は、高密度集束超音波(HIFU)を印加するように構成されたエネルギー印加装置12およびパルス発生器14を含むシステム10のブロック図である。一実施形態では、システム10は、例えば、関数発生器80、電力増幅器82、および整合ネットワーク84を含むパルス発生器を含む。本明細書で提供される実験結果を生成するために使用される一実施形態では、パルス発生器は、1.1MHzの高密度集束超音波(HIFU)トランスデューサ(Sonic Concepts H106)、整合ネットワーク(Sonic Concepts)、RF電力増幅器(ENI350L)、および関数発生器(Agilent 33120A)を含む。HIFUトランスデューサ12を、脱気水で満たされた高さ6cmのプラスチックコーンを通して動物被験体に連結した。図8は、図7のシステム10と共に使用され得るエネルギー印加装置の一例であり、本明細書で提供されるようにエネルギーを印加し、かつ標的組織を撮像するために、例えばコントローラ16によって制御され得る単一のエネルギー印加装置12内に配置されたHIFUトランスデューサ74Aと撮像用超音波トランスデューサ74Bとを含む。
臓器特異的神経調節のための超音波標的化
動物プロトコル
超音波神経調節に使用したプロトコルは以下の通りであった。
動物を2~4%イソフルランで麻酔する。
処置中の温熱療法を防ぐために、動物は水循環温暖パッドの上にうつぶせに置く。
刺激の前に、超音波刺激の指定箇所(対象神経)上の領域を、使い捨てかみそりと動物用バリカンで剃毛してもよい。
診断イメージング超音波を用いて対象領域を識別する。
肝臓は、肝門脈のドップラー同定によって示される肝門部とする。
脾臓は、診断用超音波によって脾臓を視覚的に識別する。刺激の位置は、識別された脾臓軸に沿って維持する。
後で識別できるように領域に永久マーカーを付けてもよい。
FUS超音波プローブまたはLogiQ E9プローブのいずれかを、診断用超音波で先に識別した指定の対象領域に配置する。
次に、単一の1分のパルスを超えない単一の刺激の総持続時間で超音波パルスを実施する。どの時点でも、エネルギーが熱損傷やアブレーション/キャビテーションに関連するレベルに達することはない。
その後、LPS(10mg/kg)を腹腔内注射してもよい(急性/動態研究用)。あるいは、効果の持続時間の間、LPSはここで注射せず、代わりに後に指定された時点で注射する。
2回目の1分の超音波刺激を印加する。
次いで、急性(1時間)および動態(LPS後最大3時間まで変動する)研究用に麻酔下で動物をインキュベートすることが可能になる。その後、動物を屠殺して組織、血液試料を採取する。
効果の持続時間の研究のために、LPSは超音波刺激時には注射せず、むしろ超音波刺激印加後の指定された時点(例えば0.5、1、2、4または8時間)で注射する。その後、動物を麻酔薬保持チャンバーに入れ、安楽死および組織/体液採取までモニターする。
腹膜腔の基部から延長して胸膜腔まで切開を行う。臓器(脾臓および肝臓を含む)を速やかに取り出し、ホスファターゼ(0.2mMのフェニルメチルスルホニルフルオリド、5μg/mLのアプロチニン、1mMのベンズアミジン、1mMのオルトバナジン酸ナトリウム、および2μMのカンタリジン)およびプロテアーゼ(Roche Diagnosticsによる組織1μL~20mg)阻害剤を含むPBS溶液中でホモジナイズする。PBS溶液1mL当たり組織0.2gの目標最終濃度を全ての試料に適用した。血液試料は、試料の凝固を防ぐために抗凝固剤(二ナトリウム)EDTAと共に保存した。次いで試料を分析まで‐80℃で保存する。試料をサイトカイン(Bio‐Plex Pro;Bio‐Rad)、TNF(Lifespan/Abcam/ThermoFisher)およびアセチルコリン(Lifespan)濃度の変化についてELISAアッセイで分析した。カテコールアミン濃度は、HPLC検出またはELISA(Rocky Mountain Diagnostic)分析を用いて評価した。
電極に基づく迷走神経刺激制御実験プロトコル
HPLC分析
超音波調節分子シグナル伝達経路の化学的阻害
組織抽出とパラフィンブロック変換:
次のプロトコルで(各インキュベーション中に真空と圧力で)組織を処理する。
a.70%エタノール、37℃、40分
b.80%エタノール、37℃、40分
c.95%エタノール、37℃、40分
d.95%エタノール、37℃、40分
e.100%エタノール、37℃、40分
f.100%エタノール、37℃、40分
g.キシレン、37℃、40分
h.キシレン、37℃、40分
i.パラフィン、65℃、40分
j.パラフィン、65℃、40分
k.パラフィン、65℃、40分
l.パラフィン、65℃、40分は、包埋の準備ができるまでこのパラフィンに入れたままにする。ただし、12~18時間を超えないこと。
切出しのためにパラフィンブロックに包埋し、切出し前にブロックを冷却/固化させる。厚さ5ミクロンに切出し、採取のために50℃の水浴上に浮遊させる。正電荷を帯びたスライドガラスを使用し、全てのスライドガラスについて同じ向きに組織を配置するように努める。スライドガラスを風乾させる。一晩室温におくことが乾燥させるのに最善のようであるが、スライドガラスを40℃のスライドウォーマーの上に置いて乾燥工程を早めることができる。ただし、スライドガラスをウォーマー上に1時間以上放置しないこと。スライドガラスを4℃で保存する。
IHCプロセス
画像処理
心拍数のモニタリングと分析
超音波誘導性活性化の拡散機能的MRI測定
データ分析と結果
ここで、b1=0、b2=1000s/mm2であり、S(bi)はi番目のb値における信号強度を表す。
2.実験結果
周波数:1.1MHz
パルス長:136μs
パルス繰り返し間隔:500μs(27%デューティサイクル)
総超音波照射時間:1分
焦点での推定陽圧:5MPa
焦点での推定負圧:‐2MPa
トランスデューサの幾何学形状:中心開口部を使って球状に焦点を合わせる
トランスデューサ外径:約70mm
トランスデューサ中央開口部直径:約20mm
焦点距離:約54.8mm(Fナンバー約1)
焦点スポット領域:直径1.8mm、長さ11.7mmのほぼ楕円形
Claims (1)
- 被験体の末梢組織の対象領域に超音波エネルギーを印加するように構成されたエネルギー印加装置であって、前記末梢組織がそれぞれのニューロンの複数の軸索終末を含み、前記対象領域は前記複数の軸索終末のサブセットを含み、前記軸索終末が個々の軸索終末とそれぞれの非神経細胞との間にシナプスを形成する、エネルギー印加装置と、
前記複数の軸索終末のサブセットと、関連するシナプスのサブセットを含む、組織の前記対象領域を空間的に選択し、
前記対象領域に前記超音波エネルギーを集束させ、
前記関連するシナプスのサブセットの優先的活性化を誘導して、目標とする生理学的結果を引き起こすために、1つ以上の超音波エネルギーパルスに応答して前記1つ以上の超音波エネルギーパルスを印加する前のベースライン活性に対して神経細胞と非神経細胞との間のシナプスにおける活性に変化を引き起こすよう、前記対象領域内に1つ以上のエネルギーパルスを印加することによって、前記エネルギー印加装置を介した前記対象領域への前記超音波エネルギーの印加を制御するように構成されたコントローラと
を含み、
前記コントローラが、
プロセッサと、
前記末梢組織の前記対象領域を空間的に選択する、前記対象領域に前記超音波エネルギーを集束させる、または前記超音波エネルギーの印加を制御する、またはそれらの組み合わせをプロセッサによって実行するように構成された一組の調節パラメータを含む、命令を記憶するメモリと
を備え、
前記対象領域は、神経免疫接合部を含み、前記目標とする生理学的結果は、免疫機能の刺激であり、
前記コントローラは、前記エネルギー印加装置に、一組の調節パラメータに従って前記超音波エネルギーを印加させ、前記目標とする生理学的結果の特徴を示す評価装置から受信したフィードバックに基づいて前記一組の調節パラメータを動的に変更させるようにさらに構成され、
前記生理学的結果の特徴がリンパ排液の変化である、超音波神経調節システム。
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