JP5879402B2 - 神経細胞の活動を調節する超音波発生デバイス - Google Patents
神経細胞の活動を調節する超音波発生デバイス Download PDFInfo
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Description
本出願は、2008年7月14日に出願された米国仮出願第61/080,666号および2009年5月4日に出願された米国仮出願第61/175,413の優先権を主張するものであり、それらの各々は、参照することにより本明細書に組み込まれる。
本明細書および添付の特許請求の範囲において使用される、単数形「a」、「an」、および「the」は、その文脈がそうではないことを明確に定めない限り、複数形も含む。したがって、例えば、「医薬担体」という言及は、そのような担体の2つ以上の混合物等を含む。
海馬切片培養物をthy‐1‐シナプトフルオリン(spH)マウスから調製した。シナプトフルオリンは、thy−l−spHマウスの興奮性および抑制性の両方の海馬ニューロンに発現する。これらのマウスからの個々の放出部位におけるシナプス小胞の放出(開口放出)は、共焦点レーザー走査顕微鏡から488nmのレーザー光で励起した時に、光学スペクトルの緑色の部分に特定の波長(約530nm)の蛍光を発するspHによって示される。視野内のすべての部位から蛍光発光強度(F)を測定して、シナプスの活動を定量化する。パーセンテージで表したΔFは、合計蛍光強度における変化率、すなわちシナプスの活動における変化率を示す。シナプスの活動は、CA1放線状層(CA1SR)領域およびCA1錐体細胞層(CA1SP)領域の両方でspHによって示され、後者は、抑制性シナプスの密度が特に高い領域である。したがって、spHによって示される神経活動の調節は、興奮性または抑制性の調節またはいくつかの組み合わせを示すことが可能である。
超音波調節の効果が、より侵襲性である従来手段によって誘発される神経活動の変化に匹敵するかどうかを判定するために、図6Aおよび図6Bを考察する。図6Aは、電気インパルスによる調節後、および実施形態にしたがった超音波波形による調節後の神経活動の時間応答の比較を示すグラフ600である。横軸602は秒で表した時間であり、水平スケールは5秒に相当するセグメント601によって表される。縦軸604はパーセント(%)でΔFを示しており、垂直スケールは10%に相当するセグメント605によって表される。USW‐1の開始は、チェックマーク603によって示される。曲線610は、グラフ530の平均応答540によって表されるように、148を超える個別応答から、USW‐1からの平均時間応答を示す。曲線620aは、40個の活動電位(AP)および20Hz(n=51の個々のシナプスに対して平均化)の単極電極を使用した電気刺激に対する、神経組織のSchaffer側枝領域におけるspH蛍光の応答を示す。同様に、曲線620bおよび620cは、それぞれ、100AP/20Hz(n=63)および250AP/50Hz(n=48)の単極電極を使用した電気刺激に対するSchaffer側枝におけるspH蛍光の応答を示す。
機械的エネルギー(例えば、音波)の吸収によってもたらされる膜張力の変化は、ニューロンの脂質二重層の弾性および膜貫通タンパク質のばね様機構のために、個々のニューロンの活動を変更する。実際に、多くの電位開口型イオンチャネル、および神経伝達物質受容体は機械感受性を持つため、膜張力の変化によって特異的に開口されることを可能である。したがって、超音波によって神経活動に付与される機械的エネルギーの影響を調査するための一連の方法が用いられた。これらの方法を使用して、パルス状の超音波が、SNARE媒介性シナプス伝達、ならびに中枢ニューロンにおける電位開口型ナトリウム(Na+)チャネルおよび(カルシウム)Ca2+チャネルを刺激することができることが見出された。SNAREタンパク質は、シナプス伝達および小胞の開口放出に関与する、ニューロンのシナプトブレビン(n‐Syb)、SNAP‐25およびシンタキシンlA(Syx 1A)、ならびにシナプトタグミンI(Syt I)を含む、タンパク質の分類である。
当該技術分野で知られているように、野生型マウスから調製した培養物にNa+インジケーターであるCoroNa Green AMを使用したところ、USW‐1がCA1錐体ニューロン(CA1SP)においてNa+濃度変化を引き起こすことが見出された。図8は、1つの実施形態にしたがって、超音波波形による調節後に神経細胞のNa濃度変化に与えられる、例示的な時間的影響を示すグラフ810である。横軸812は秒で表した時間であり、水平スケールは5秒に相当するセグメント811によって表される。縦軸814は、CoroNa GreenによるΔFをパーセント(%)で示し、垂直スケールは4%に相当するセグメント815によって表される。USW‐1の開始は、チェックマーク813によって示される。各超音波波形の後のNa濃度変化の個別応答をトレース820で表し、平均応答を曲線822で示す。最大応答は、n=18測定に対してΔF/Fo=5%±0.6%であった。個別応答840によって示されるように、この応答はテトロドトキシン(TTX)の添加により遮断された。
超音波によって引き起こされるCa2+濃度変化が、主に電位開口型Ca2+チャネルによって媒介されるかどうかを判定するために、Cd++を添加して電位開口型Ca2+チャネルを遮断した。500μMのCd++を添加したところ、USW‐1に応答するOGB‐1信号をほとんど無効にした。同様に、TTXを添加すると、USW‐1によって生成されるOGB‐1信号の約85%を遮断した。図10は、1つの実施形態にしたがって、超音波波形を用いた調節によって神経細胞のシナプス前活動に与えられる例示的な時間的影響を示すグラフ1030である。横軸1032は秒で表した時間であり、水平スケールは5秒に相当するセグメント1031によって表される。縦軸1034はOGB‐1のΔFをパーセント(%)で示し、垂直スケールは70%に相当するセグメント1035によって表される。USW‐1の開始は、チェックマーク1033によって示される。曲線1040は、神経組織にプロセス阻害剤を導入しない場合の、OGB‐1のUSW‐1に対するシナプス前平均時間応答を示す。曲線1050は、Na+の透過性を阻害するためにTTXを添加した場合の平均時間応答を示しており、TTXはUSW‐1の効果をほとんど無効にした。曲線1060は、電位開口型Ca2+チャネルを遮断するためにCd++を添加した場合の平均時間応答を示しており、同様に、Cd++はUSW‐1の効果をほとんど無効にした。Cd++またはテトロドトキシン(TTX)によって遮断されない残りのCa2+濃度変化は、NMDAまたはTRPC1受容体等の他のCa2+源に関与する可能性があり、興味深いことに両方とも機械感受性を持ち、海馬ニューロンに発現する。短い持続時間の超音波波形(例えば、f=0.44MHz、PL=0.18ms、c/p=80、PRF=10Hz、およびNp=3)を使用して、より速い速度のニューロンにおけるCa2+濃度変化を観察した(24個の試料でΔF/FO=38%±2%)。
無傷の運動野の経頭蓋超音波(US)刺激を行うために、腹腔内投与したケタミン−キシラジンカクテル(ケタミン70mg/kg、キシラジン7mg/kg)を用いてマウスを麻酔した。マイクロダイセクション用の鋏を用いて運動野に相当する領域上の頭部背側面の毛を刈り込んだ。次いで、マウスをCunninghamマウス固定装置に乗せ、防振台に固定した。固定集束ガイド付きの超音波トランスデューサを、標準座標系を使用して同定した運動野に相当する皮膚の上の位置まで下げた。次いで、集束管を運動野の上の皮膚の背側面に乗せ、超音波結合ゲルを使用して皮膚に音響的に結合した。標準的なTTLトリガプロトコルと、関数発生器を起動するためにpClampソフトウェア(Molecular Devices社製)を使用して制御したPCに接続されたデジタルI/Oデバイス(Digidata 1440、Molecular Devices社製、Sunnyvale,CA,USA)とを使用して、標的である運動野にパルス状の経頭蓋US刺激波形を送達した。TTLシグナルマーカーで、US刺激波形の開始および長さを示した。標準的なウェブカメラを使用して刺激試行のビデオ録画を取得した。刺激試行中に、電気生理学的データ(マルチユニット活動(MUA)、LFP、およびEMG)を取得した(下記参照)。刺激後、動物を麻酔から回復させるか、または下記の物質および方法でプロセスした。
横方向に集束させたUS刺激波形(n=5匹のマウス)によって活性化された運動野の面積を判定するために、c−fos標識化技術を使用して試験を行った。ANOVAは、隣接する非標的運動野および一次体性感覚野(S1)(F4,45=17.1、P<0.001、図24A)と比較して、標的運動野の活性化細胞に有意に高い密度を明らかにした。さらなる濃度測定分析により、隣接する非標的S1と比較して、標的M1の活性化細胞に有意に大きなクラスタが見られた(標的M1のクラスタ面積=9.45±1.81mm2、非標的S1のクラスタ面積=3.01±1.54mm2、T−検定、P<0.05、24B)。活性化した面積の大きさは、実施したUS波長(脳組織においておよそ3〜6mm)と、集束ガイドによって発生させられたUS刺激波形の横方向に限定的な空間的エンベロープによって生成された音圧場の面積とに一致する。(およそ8〜10mm2、図25)。
低強度の経頭蓋USが無傷の中枢神経系(CNS)の活動に与える影響を判定するために、それが既知の下行皮質脊髄の運動回路に与える影響を調査した。運動野へのUS刺激波形の経頭蓋送達に応答した筋活動の針筋電図(EMG)による記録を取得した(n=43匹のマウス、図18Dおよび18E)。例えば、図18Dにおいて、外略図(上)は、経頭蓋超音波を用いて下行皮質脊髄路を刺激するための実験手法を示す。右の経頭蓋M1刺激に応答する生筋電図(EMG)のトレースは、USによって誘発された左上腕三頭筋の活動を示している。図18Eは、自発的(上)および平均(10試行)のUS誘発(下)事象の生EMG(左)および全波整流(FWR、右)EMGのトレースを示す。US刺激波形の持続時間(黒)、USによって誘発されたEMGのトレースの平均(グレー)、およびEMGの積分値(緑)を右下に重ね合わせた。
しかしながら、低強度のパルス状超音波が脳の温度に与える影響を評価するために、音響強度およびパルス持続時間(PD)を変化させて経頭蓋超音波を送出しながら運動野の温度を監視した。生物組織におけるUSの熱吸収を推定するための方程式から、0.57ミリ秒のPDの間に0.097MPaのprをもたらす0.5MHzのUSパルスは、脳において2.8×10−6℃の温度上昇を誘発することができると予測した。簡単に言うと、最大温度変化(ΔTmax)は次のように予想され、
US刺激波形の音響周波数および強度が、どのように神経回路活動に影響を与えたかを判定するために実験を設計した。4つの異なるUS周波数(0.25、0.35、0.425、0.500MHz)が、マウスの上腕三頭筋によって生成されるEMGの振幅に与える影響を検討した(n=20)。二元配置ANOVAによって、周波数が低いほど、よりロバストなEMG応答をもたらすという、US周波数がEMG振幅に与える有意な主効果を明らかにした(F3,1085=3.95,P<0.01)(図19E)。US刺激波形の強度が、神経活動にどのように影響するのかをよりよく理解するために、パルス強度積分値(PII)およびパルス繰り返し周波数(PRF)の両方が考慮される音響強度測定値に焦点を合わせた。検討した上記音響周波数の範囲にわたって、異なるISPTA値を有する20個の個別の波形を調べた(表2)。二元配置ANOVAはまた、ISPTAがEMG振幅に与える有意な主効果を明らかにし(F19,1085=9.78、P<0.001、図19F)、ISPTA値が低いほど、より大きなEMG振幅を引き起こすことを示唆した。具体的には、図19Fは、20個の異なる刺激波形によって生成されたUS強度(ISPTA)の関数としてプロットした、正規化したUSによって誘発されるEMG振幅を示す。図2Gには、US強度(ISPTA)とUS周波数の間の交互相互作用が、正規化したEMG振幅の関数としてプロットされており、また二元配置ANOVAも、周波数と強度の有意な交互作用を明らかにした(F3,1085=7.25、P<0.01)。総じて、これらのデータは、低強度、低周波の経頭蓋USが、無傷の動物における皮質回路の活動を促進するのに効果的であることを示唆している。
パルス状US刺激波形の強度特性を評価するために、US圧力波によって生成された電圧トレースを、較正したニードル型ハイドロフォン(HNR 500、Onda Corporation社製、Sunnyvale,California,USA)およびPCに接続したAgilent DSO6012A 100MHzデジタルオシロスコープを使用して記録した。トランスデューサが意図する音響周波数で動作していることを確認するために、US波形に応じて記録されたハイドロフォンの電圧トレースに対してFFTを行った。xyzマイクロマニピュレーター(MP−225,Novato,CA,USA)を使用してUS音場にわたってハイドロフォンの位置を走査し、集束ガイドを使用して新鮮な体外頭部(無傷の毛、皮膚、頭蓋、および硬膜)を介して送出された圧力を記録することにより、すべての強度測定を遠場において行った。より具体的には、強度測定は、運動野頭蓋表面から0.8mm下の運動野に相当する位置、および体外頭部を透過させることなく、トランスデューサの面から同じ距離の位置で行った(図22)。経頭蓋US波形は、直径5mmのポリエチレン管、または出力側で直径2mmに先細りになった直径5mmの管から構成される特別に設計した横方向集束ガイドを使用して、USトランスデューサから無傷の運動野に送出した(図25)。集束ガイドは超音波結合ゲルで充填した。
いくつかの実験手法を実施して、超音波が細胞の基礎構造および脳血管系に与える影響を検討した。そのようなすべての実験の前に、10秒のITIで20分超繰り返した比較的高い強度のUS刺激波形(表2を参照)を運動野に送達した。定量透過電子顕微鏡を使用して、運動野における興奮性シナプスの超微細構造を調べた。電子顕微鏡のために組織を調製して、標準的手段を用いて撮像を行った。刺激した後で、カコジル酸ナトリウム緩衝液中の2%グルタルアルデヒド、2.5%ホルムアルデヒドで動物を経心的に灌流した。続いて脳を取り出し、カコジル酸ナトリウム緩衝液中の2%グルタルアルデヒド、2.5%ホルムアルデヒドで一晩4℃で後固定した。後固定した後で、カコジル酸ナトリウム緩衝液で脳を3回洗浄し、ビブラトームを使用して300μmの薄片にスライスした。運動野を含む切片を特定し、カコジル酸ナトリウム緩衝液で5回(各15分)洗浄し、一晩かけて最終洗浄した。翌日、室温で1時間、カコジル酸ナトリウム緩衝液中の0.2%四酸化オスミウムで2回目の固定を行った。0.25%酢酸ウラニルを用いて一晩4℃でブロック染色を行う前に、カコジル酸ナトリウム緩衝液中で薄片を3回および水中で3回洗浄した。勾配20%、40%、60%、80%、および100%の一連のエタノールで試料を脱水し(各3回洗浄)、最終的に100%アセトン中で2回洗浄することにより脱水した。テフロン(登録商標)で被覆したスライドガラス上に平板包埋して60℃で一晩重合させる前に、3日間試料をSpur’s樹脂中で25%、50%、75%、および100%浸潤させた(各3回インキュベーション)。
別の一連の実験において、脳血管系の完全性を検討した。実験前に、正常条件下では血液脳関門(BBB)を通過しないフルオレセインイソチオシアネート‐デキストラン(10kDa)をマウスに静脈内投与した。共焦点顕微鏡を使用した標的化皮質の刺激後分析において、US刺激波形は脳血管系に損傷をもたらさず、また血液脳関門を破壊しないことが観察された(対照=皮質面積353.35cm2および血管系長17.96cm(5匹のマウスよりテスト)、超音波刺激=皮質面積352.96cm2および血管系長18.34cm(5匹のマウスよりテスト))。
行動試験を利用する実験において、運動野のUS刺激が、協調、バランス、平衡、および握力に与える影響を評価するために一連の行動分析を行った。超音波刺激を行ったマウスと偽処置対照マウスを、ロータロッドタスクおよびワイヤ懸垂タスクを使用する行動試験に供した。両グループとも、処置の24時間前に、両方のタスクについて処置前ベースライン試験を行った。処置当日に、偽処置対照およびUS刺激を与えた動物を、ケタミン/キシラジンを用いて麻酔し、前述したように毛を刈り込んだ。超音波刺激または偽処置の後、ロータロッドおよびワイヤ懸垂タスクの運動能力試験を実施し、24時間後および7日後に再び実施した。各試験日に、動物は、ロータロッド(外周25.4cm、幅10.8cmのロッド)の上を、2種類の速度(17および26RPM)でそれぞれを5試行ずつ、失敗するまで(ロータロッドから落ちるまでの時間を秒で表す)走行した。ロータロッド試行の後で、動物は、失敗する時まで(吊り下げられたワイヤから落ちるまでの時間を秒で表す)ワイヤ懸垂試験を5試行分行った。ワイヤ懸垂タスクでは、地面から51.0cm上に吊るしたワイヤ(長さ76.2cm×直径0.16cm)からマウスを前肢で吊り下げた。各試験日の各タスクについて、5試行のそれぞれからのデータを平均化した。
音圧の力学的波特性は、これらの脳液に影響を与える。USの局所的作用について、細胞外空間が連続的な媒質であると考えることができる。クヌーセン数の検討(Kn=λ/L、式中、λは分子の平均自由行程であり、Lは対象となる物理的境界の代表長さスケール)。したがって、USが脳の細胞外空間において脳脊髄液(CSF)の動態に与える影響について、水のλ(およそ10−11m)が、CSFのλについての妥当な推測値を提供する(特に、CSF中に見られる大きな分子のタンパク質および頭蓋内圧が、λ値をさらに減少させることを考慮する)。次いで、脳内の細胞の間の細胞外空間(L)がおよそ10−8mであると見なすと、0.001というKn値が算出される。Knが1未満である時、連続体力学の定式化(Kn≫1である量子力学とは反対)が妥当であり、適用することができる。さらに、連続的細胞外空間と、脳内のニュートン流体(CSF)および非ニュートン流体(粘弾性細胞膜)両方の存在との組み合わせが、この見解を支持する。USは、脂質二重層、周辺の細胞内/細胞外流体、および交互になった脳血管系の間の音響インピーダンスのわずかな不整合(境界条件)から生じる音響放射圧、せん断応力、ベルヌーイ効果、および他の流体力学的帰結に加えて、安定した空洞化および音響流(マイクロジェット形成、渦、および乱流)を伴う圧力/流体/膜の作用の組み合わせによって、神経活動を非侵襲的に調節することができる。
Claims (11)
- 神経細胞の活動を調節する超音波発生デバイスであって、
調節される神経細胞の部位に刺激波形を送達するべく構成された、超音波を発生させる少なくとも一の構成要素を含み、
前記刺激波形は、各パルスが超音波周波数の一以上のサイクルを含む複数のパルスを含み、
前記複数のパルスの各パルスが複数の周波数を含み、
各パルスが0.001m秒から10秒の範囲のパルス持続時間を有し、
前記複数のパルスが、0.001から10kHzの範囲のパルス繰り返し周波数で繰り返され、
前記超音波を発生させる少なくとも一の構成要素は、アナログ又はデジタル波形を使用して駆動される、デバイス。 - 前記超音波を発生させる少なくとも一の構成要素は、超音波エミッタ、超音波トランスデューサ、圧電超音波トランスデューサ、複合トランスデューサ、静電容量型微細加工超音波トランスデューサ、若しくはこれらの組み合わせ、又はアレイ構成を含む、請求項1に記載のデバイス。
- 前記刺激波形は焦点方式又は非焦点方式で送達される、請求項1又は2に記載のデバイス。
- 前記刺激波形は、方形波、正弦波、鋸波状波形、スイープ波形、若しくは任意の波形、又は一以上の波形の組み合わせを含む、請求項1から3のいずれか一項に記載のデバイス。
- 前記超音波を発生させる少なくとも一の構成要素は1から1000個の超音波トランスデューサ要素を含む、請求項1から4のいずれか一項に記載のデバイス。
- 前記複数のパルスは、周波数及び持続時間が異なるパルスを含む、請求項1から5のいずれか一項に記載のデバイス。
- 対象の細胞活動の調節をすることに使用されることを目的として、少なくとも一の刺激波形を形成する超音波を発生させる構成要素を形成するべく適合され、
(i)前記構成要素は前記対象に音響的に結合されるべく適合され、
(ii)前記調節がされる細胞の部位において前記刺激波形は、450mW/cm2、400mW/cm2、350mW/cm2、300mW/cm2、250mW/cm2、200mW/cm2、150mW/cm2、100mW/cm2、50mW/cm2、又はこれらに記載の量以内のレベルの強度の一以上を含み、
(iii)前記刺激波形は、0.02から1MHzの範囲の一以上の周波数を含む、請求項1から6のいずれか一項に記載のデバイス。 - 前記刺激波形の複数のパルスはそれぞれ、0.1から0.9MHzの範囲の複数の周波数を含む、請求項1から7のいずれか一項に記載のデバイス。
- 前記超音波を発生させる少なくとも一の構成要素は、中心周波数を有する超音波トランスデューサを含み、
前記超音波トランスデューサは、共振周波数の導入を避けるべく前記中心周波数からずれた基本周波数で駆動されるべく構成され、
前記超音波を発生させる少なくとも一の構成要素には、前記刺激波形を発生させることが許容され、
各パルスは複数の周波数成分を導入する、請求項1から8のいずれか一項に記載のデバイス。 - 前記複数の周波数成分は、前記基本周波数と、前記基本周波数のうなり周波数又は前記基本周波数の調波周波数の少なくとも一方とを含む、請求項9に記載のデバイス。
- 前記複数のパルスは、100W/cm2未満の空間ピーク時間平均強度をもたらすべく前記0.001から10kHzの範囲のパルス繰り返し周波数で繰り返される、請求項1に記載のデバイス。
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