We would like to thank everyone at Shriners Hospital Pediatric Research Center, in particular Dr. Mickey Seltzer, of whom without his support, this work would not have been funded. In addition, we would like to thank Isha Srivastava, who contributed to early data collection and Amy He, who helped with the figures. This study was funded by Shriners Hospitals for Children. No funding source played a role in experimental design or decision to submit the paper for publication.

<ol>
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The authors declare that they have no competing financial interests.

人間とげっ歯類の間で行わ行動試験は、ヒトの症状に直接関連性を持っている細胞および分子応答の間に重複がある場合ヒトの疾患を研究するための動物モデルを使用するとのみ関連します。小児疾患の研究の主な問題の一つは、多くの研究者が疾患プロセスのために重要であり得る発達の違いを考慮することなく、モデル、ならびに成体げっ歯類の行動評価を作成するために、成体げっ歯類を使用することです。 、7（7日間の齧歯類- - 32週出生後2日目に相当し28で例えば、ヒトCNSの開発）、これらの問題のため、小児疾患の利用に関する研究だけではなく、適切な調整後の発達時点があることが重要ですだけでなく、適切な運動、感覚や反射的発達行動を検討する行動試験を。それぞれの新しい新生児疾患モデルが開発されるようにこのように、厳密に携帯することを保証するために試験されなければなりませんそして、行動反応は、齧歯類とヒトの間で最も適切な翻訳可能なデータを提供します。 脳性麻痺は、大人になって存続運動障害、です。現在入手可能な脳性麻痺モデルの多くの1つの問題は、小児患者に見られる障害と相関することができ、再現、標準化された運動テストの欠如です。新生児マウスにおいて低酸素症、虚血、および炎症を組み合わせたこの新たなモデルでは、モータの動作は、新生仔マウスに特異的な一連の試験を用いて評価しました。主観性を減少させ、定量的な報告を高めるために、いくつかの試験は非常に特異的ではなく、標準化することができる措置を評価しやすい含むように修飾されています。また、フロント及び後肢評価を別々に行うことができ、右/左の差を決定することができます。テストのこの電池は、年齢の2週間まで新生仔マウスに特異的です。 このCPモデルは示しています歩行困難（歩行、後肢蹄の角度）、ならびに四肢固有の弱点（4肢のサスペンション、後肢懸垂）、および発達反射の欠損（反射を把握）。この研究において唯一の時点を調べたが、これらの障害は、時間の経過とともに追跡することができます。 そのような試験のフォックスのバッテリーや発達のマイルストーン15のHeyserの評価として、新生児に使用することができるテストの他の電池は、あります。しかし、これらのテストは、その応答新生児がまだ開発されているので、同じではないかもしれない大人に新生児を比較します。フォックスのバッテリーとHeyserのAssementテストが観察主観的な二分法との情報（yesまたはno）の評価ではなく、客観的なデータ（角度、強度などに基づいて姿勢）に依存しています。そのため、これらの試験の主観性のため、多くの科学者は、このように他の人と限界への比類のない、その結果を作り、基準を、適応追加、または削除しました特定の疾患または障害のベースライン赤字を確立するという点で、データの有用性をる。定性的および特に新生児をテストするために設計されている標準化された運動テストの一組を確立することにより、個々の研究グループからの結果を正確かつ確実に報告し、比較することができます。

げっ歯類を用いた小児傷害または疾病の新モデルを開発することにより、急速に神経損傷から回復するラットとマウスの両方の驚くべき能力にしばしば困難です。したがって、任意の新たな小児疾患モデルを検証するために、徹底的に細胞および分子の変化を調べることは、行動転帰と手に手を行く必要があります。多くの点で、機能的な行動回復は、治療または翻訳関連性の面で根本的な細胞の変化よりも重要な場合があります。研究者は、成人と新生児における傷害についての詳細を学ぶように、彼らの応答が非常に異なっており、両者の間に外挿することはできないことは明らかです。例えば、新生仔マウスは、神経成長因子、脳由来神経栄養因子、ニューロトロフィン3及び脊髄損傷1,2次グリア細胞株由来神経栄養因子の異なるレベルを表示します。また、新生児は、脳卒中3、Dの後、有意な血液脳関門漏出を有します末梢神経損傷4の後emonstrate皮質ニューロンの再配置、および遅延または脊髄損傷および低酸素虚血5,6次アストログリオーシスを遅らせてきました。したがって、並進小児科の研究が発達同等のモデルを使用し、それらのモデルは、分子/細胞の変化と年齢に応じた行動試験の両方で評価されることことが重要です。 毎年1000年出生（NIH）：脳性麻痺（CP）が3に影響する運動障害です。 CP児は、疾患の重症度に応じて、症状や合併症の条件の範囲を示します。運動と協調の難しさは、モータの発達のマイルストーンに到達するの遅れに伴い、最も一般的な兆候です。他の徴候は、異常な筋緊張を（増加または減少のいずれか）が含まれ、細かい運動能力、歩行困難、過度のよだれや嚥下、音声遅延（NIH）を減少させました。 CPの根本的な原因はあると考えられています、または1年間の産後までの前または周産期中の酸素および/または脳への血流の欠如。さらに、炎症は、現在CPの開発における重要な要素であると考えられています。 CPの例大半は脳室周囲白質軟化症（PVL）として知られる心室、周りの白質損傷に関連しています。この神経学的特徴は、CPに至る初期の侮辱は、オリゴデンドロサイトが傷害に対して最も脆弱な脳の発達の期間中に発生したことを示唆しています。 32週の妊娠 - 人間の急速なオリゴデンドロサイトの成長の期間、オリゴデンドロサイトが傷害に最も影響を受けやすいもの期間は、24の間です。げっ歯類では、同等の期間は、出生後の日2 - 7 7、およびCPは、このモデルにおいて誘導されたときです。 ここで概説試験を実施するために使用されたCPの新生児マウスモデルは、INJを作成するために、炎症と低酸素症および虚血を兼ね備えより良い模倣人間CPで見られる神経変性ユリィ。このモデルは、人間のCP患者に似た個別の運動障害、ならびに個別の白質損傷を欠いているCPの他の動物モデルにおいて観察された主要な欠点のいくつかに対処しています。同じモデルを使用して、共同研究者による以前の研究では、このように優れたCP 8と子供に見られるPVLをエミュレートし、炎症の添加は白質の損傷を増強することを実証しました。以前のデータを踏まえ、本稿では、動物の年齢などの運動行動の変化を評価するために、新生児モータの総合テストバッテリーを提示します。

<table border="0" cellpadding="0" cellspacing="0" width="1354">
	<tbody>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">C57BL/6 mice</td>
			<td style="width:239px;">Charles River Laboratories</td>
			<td style="width:103px;">STRAIN CODE: 027&#160;</td>
			<td style="width:741px;">C57BL/6NCrl is the exact strain we use</td>
		</tr>
		<tr height="60">
			<td height="60" style="height:60px;width:271px;">Anesthesia Dish, PYREX&#8482; Crystallizing Dish</td>
			<td style="width:239px;">Corning Life Sciences Glass&#160;</td>
			<td style="width:103px;">3140125</td>
			<td style="width:741px;">Capacity: 25.03 oz. (740mL); Dia. x H: 4.92 x 2.55 in. (125 x 65mm). However, any small round glass container will work. A 2 cup capacity pyrex food storage bowl with flat bottom will also work and is much cheaper (Pyrex model number: 6017399).</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Covered lead ring</td>
			<td style="width:239px;">Fisher Scientific</td>
			<td style="width:103px;">S90139C</td>
			<td style="width:741px;">Lead ring for stablizing flasks in a water bath. It is used inside the anesthesia dish.</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Scalpel Blade #11</td>
			<td style="width:239px;">World Precision Instrucments, Inc.</td>
			<td style="width:103px;">500240</td>
			<td style="width:741px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Small Vessel Cauterizer</td>
			<td style="width:239px;">Fine Science Tools</td>
			<td style="width:103px;">18000-00</td>
			<td style="width:741px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Micro Hook</td>
			<td style="width:239px;">Fine Science Tools</td>
			<td style="width:103px;">10064-14</td>
			<td style="width:741px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Vetbond Suture Glue</td>
			<td style="width:239px;">3M</td>
			<td style="width:103px;">1469SB</td>
			<td style="width:741px;">n-butyl cyanoacrylate adhesive</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Lipopolysaccharide</td>
			<td style="width:239px;">Sigma Life Science</td>
			<td style="width:103px;">L4391</td>
			<td style="width:741px;">Lipopolysaccaride from e.coli 0111:B4, gamma irradiated</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:271px;">12x12 inch opaque box</td>
			<td style="width:239px;">Acrylic Display Manufacturing: A division of Piasa Plastics</td>
			<td style="width:103px;">C4022</td>
			<td>Colored Acrylic 5-Sided Cube, 3/16&#34; Colored Acrylic, 12&#34;W x 12&#34;D x 12&#34;H;&#160; http://www.acrylicdisplaymfg.com/html/cubes_19.html</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:271px;">Camera/camcorder</td>
			<td style="width:239px;">JVC</td>
			<td style="width:103px;">GC-PX100BUS</td>
			<td style="width:741px;">Any camcorder that works well in low light and can be imported and edited. We use the JVC GC-PX100 Full HD Everio Camcorder.</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">Covidien Tendersorb&#8482; Underpads</td>
			<td style="width:239px;">Kendall Healthcare Products Co</td>
			<td style="width:103px;">7174</td>
			<td style="width:741px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:271px;">WypAll L40</td>
			<td style="width:239px;">Kimberly-Clark Professional</td>
			<td style="width:103px;">5600</td>
			<td style="width:741px;">Any surface with moderate grip will do</td>
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			<td height="20" style="height:20px;width:271px;">Surface at 45 degree incline</td>
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			<td style="width:741px;">We use a cardboard box.</td>
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			<td height="20" style="height:20px;width:271px;">Thin wire from a pipe cleaner</td>
			<td style="width:239px;">Creatology</td>
			<td style="width:103px;">M10314420</td>
			<td style="width:741px;">Any pipe cleaner from any craft store will work.</td>
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			<td height="20" style="height:20px;width:271px;">50mL conical tube</td>
			<td style="width:239px;">Falcon</td>
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			<td style="width:741px;">Any supplier can be used as long as their screen is 16x16 or 18x16</td>
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			<td height="20" style="height:20px;width:271px;">Razor blade</td>
			<td style="width:239px;">Fisherbrand</td>
			<td style="width:103px;">12-640</td>
			<td style="width:741px;">A wooden stick applicator or wooden part of a cotton-tipped swab will also work.</td>
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			<td height="100" style="height:100px;width:271px;">OPTIX 24-in x 4-ft x 0.22-in Clear Acrylic Sheet to make Clear Acrylic Walkway</td>
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			<td style="width:741px;">Clear acrylic (1/8&#34; thick) with sides and a top to limit exploration. We bought a sheet of acrylic from a local hardware store and had them cut it to size. (2) 2&#34;x2&#34;; (3) 2&#34;x 18&#34;; (1) 2&#34;x15.5&#34;; (1) 2&#34;x3&#34;. Using clear tape, tape all sides together, with the 15.5&#34; piece on top. Tape the 3&#34; piece to the end of the 15.5&#34; piece to create a flap/entryway for the mice. Alternatively, part or all of the walkway can be glued together, and only taping on the top pieces. This design will allow for the walkway to be opened for easy cleaning.</td>
		</tr>
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			<td height="20" style="height:20px;width:271px;">Protractor</td>
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</table>

a battery of motor tests in a neonatal mouse model of cerebral palsy

As the sheer number of transgenic mice strains grow and rodent models of pediatric disease increase, there is an expanding need for a comprehensive, standardized battery of neonatal mouse motor tests. These tests can validate injury or disease models, determine treatment efficacy and/or assess motor behaviors in new transgenic strains. This paper presents a series of neonatal motor tests to evaluate general motor function, including ambulation, hindlimb foot angle, surface righting, negative geotaxis, front- and hindlimb suspension, grasping reflex, four limb grip strength and cliff aversion. Mice between the ages of post-natal day 2 to 14 can be used. In addition, these tests can be used for a wide range of neurological and neuromuscular pathologies, including cerebral palsy, hypoxic-ischemic encephalopathy, traumatic brain injury, spinal cord injury, neurodegenerative diseases, and neuromuscular disorders. These tests can also be used to determine the effects of pharmacological agents, as well as other types of therapeutic interventions. In this paper, motor deficits were evaluated in a novel neonatal mouse model of cerebral palsy that combines hypoxia, ischemia and inflammation. Forty-eight hours after injury, five tests out of the nine showed significant motor deficits: ambulation, hindlimb angle, hindlimb suspension, four limb grip strength, and grasping reflex. These tests revealed weakness in the hindlimbs, as well as fine motor skills such as grasping, which are similar to the motor deficits seen in human cerebral palsy patients.

マウスは、試験のパラダイムを学ぶことは交絡変数ではなかったように、各時点に別のマウスを用いて、P13（1週間以下の手術）にP7（手術後24時間）から試験しました。マウスは、この時点で最大の赤字を示したようP8は、代表的な結果として選択しました。 クロールからウォーキングへの移行は、CP新生児マウスにおける遅延され 人間のCP患者はつま先歩きからシザリング歩行に至るまで、歩行異常を持っています。このCPモデルディスプレイは人間に似赤字を歩行したように、歩行を評価しました。マウスはまっすぐ歩行中の歩行対称性と肢足の動きに採点しました。 CP 1.083±：手術後48時間（PND 8）では、CPのマウスは、それらの偽の対応（平均歩行スコアと比較して少ない対称性四肢運動と「クロール」歩行を持っていました偽1.639±0.4859対0.6337、N = 12、N = 9; P &lt;0.05、 図10）。一週間では、CPおよび偽マウスの両方が（データは示していない）歩行に移行しました。 <img alt="図10" src="/files/ftp_upload/53569/53569fig10.jpg" /> 図10. CPマウス子犬は歩行しないだけでなく、シャムス。シャムマウス（黒棒）は1.639±0.4859の平均スコアを持っていた（n = 9）、彼らの歩行発達を意味する非対称性四肢運動と遅いクロールの間に入ります。 CPマウス（灰色のバー）1.083±0.6337（N = 12）の平均スコアを受け、彼らの歩行は発展途上であり、非対称の四肢の動きを持っている傾向があるという意味。データは、平均±SEMとして表されます。 *はp &lt;0.05である。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53569/53569fig10large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> ホアヒンフット角度はCPで増加するdlimb 歩行に加えて、後肢足角を評価しました。八日齢の偽の仔マウスは、直線（ 図2の中を歩いたときに後足をスプレイしているHILマウスに比べ、前方を向いた彼らの後足で歩く;平均角度：CP 77.48±9.848、N = 9、対54.54±シャム8.043、N = 11; P &lt;0.0001、 図11）。子犬が彼らの歩行を安定化し、バランスと協調を支援するために、その後部足の角度を大きくする必要があるという点で、この増加した角度は、歩行不安定性と相関します。 <img alt="図11" src="/files/ftp_upload/53569/53569fig11.jpg" /> 図11. CPマウス子犬スプレイは、彼らの後足ウォーキング。CPマウス（黒棒）77.48±8.043（N = 11）の彼らの後肢間の平均角度を持って、偽マウス（グレーBしばらく<html> ARS）は54.54±9.848（平均角度を持っているのn = 9）。データは、平均±SEMとして表されます。 ****はp &lt;0.0001である。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53569/53569fig11large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> CPのマウスは、赤字を表示しないときに表面復原 いくつかのCP患者は、トランク制御（Heyrman ら。、2013）が損なわれているように、テストを正す面が含まれていました。また、前庭系は、立ち直りの必要性を検出する必要がある、いくつかのCP患者23内の前庭障害があります。シャム対照と比較して、立ち直り時CPマウスは有意な障害を示していない（データは示さず）。 CPのマウスは、負の走地性テストにシャムと同じを実行します 。。 &quot;FO：キープtogether.within-ページは=&quot;トン配向上り坂に1 &quot;&gt;負の走地性は若い子犬に運動協調をテストするために使用されたマウスは、傾斜面に下り坂面した場所であることによってチャレンジする遅延や障害が障害を示している可能性があります（データは示していない）偽のマウスと比較して、負の走地性でチャレンジした場合に協調、バランス、または前庭入力に。CPマウスは全く障害を示さない。さらに、CPマウスは再配向もうに対して一方側に回転する選好を示しませんでした。 フロントリム懸垂試験は、10日より前のマウスに適しています CP患者は、このような把握などの細かい運動能力、で筋肉の緊張と赤字が低下しています。このマウスモデルの弱点をテストするために、我々は、フロント肢懸垂試験を用います。さらに、このモデルは、一方的な虚血性傷害を使用して両面らしこの懸濁試験を用いて決定することができます。このテスト10日15歳以上のマウスのためのより良いです。 8日齢に、損傷後2日、CPおよび偽マウスの間に有意差はなかった（データは示さず）。 後肢強度は、CPマウスにおいて減少します 人間のCP患者はしばしば、モータ制御と強度不足にブレースや支援歩行デバイスが必要です。ヒトへのげっ歯類CPモデルを比較するために、後肢強度は後肢懸垂試験を用いて評価しました。 CP 3.468±0.5561、N = 13、対偽3.891±0.1329、N = 13; pは&lt;：コニカルチューブの側面から吊り下げたときのスコアをぶら下げの減少により示されるように、CPマウスは後肢吊りスコア（、後肢弱さを示しました0.05、 図 12）。差異は後肢懸垂時間で観察されなかった（データは示さず）。したがって、ヒトのCP患者と同様に、CPマウスはhindlを実証しますIMB（脚）脱力。 <img alt="図12" src="/files/ftp_upload/53569/53569fig12.jpg" /> 図12.シャムマウスは 、偽マウス（黒棒）より後肢分離し、したがって強い後肢の姿勢を示し3.891±0.1329の平均吊りスコアで。少しけど （N = 13）CPマウスよりも彼らの後肢で有意に強いです 3.468±0.5561（N = 13）の平均吊りスコアでCPマウス（灰色のバー）よりもチューブの端にぶら下がったとき。データは、平均±SEMとして表されます。 *はp &lt;0.05である。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53569/53569fig12large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> 握力は、次のCP傷害低減されます すべての4つの足で把握することで、げっ歯類のために重要です登山や凹凸面全体に実行されているという点。グリップは、主桁で、重要な持続的な強さではなく、器用さや直線力を必要とし、24を PAWS。マウスを反転ワイヤメッシュスクリーン上に彼らの体重を保持するために必要でした。 CPマウスは彼らのグリップを維持することができませんでしたし、これらのマウスは、有意に低い角度で落ちた（四肢平均角度：CP 75.627±24.48、N = 11、対偽96.57±10.836、N = 9; P &lt;0.05、 図13）。このデータは、CPマウスにおける握力の有意な欠陥があることを示します。 <img alt="図13" src="/files/ftp_upload/53569/53569fig13.jpg" /> 13. CPマウスがシャムス。シャムマウス（黒棒） よりも弱いグリップを持っている図は、96.57±10.836の平均反転角度に把握（N = 9）ことができます。 CPマウス（灰色のバー）が唯一の75.627±24.48（N = 11）の反転角度に到達することができます。データは、平均±SEMとして表されます。 * pは0; 0.05。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53569/53569fig13large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> 把握反射赤字はCPマウスにおいて明らかです 総運動障害に伴い、微細運動の動きはまた、CP患者25,26に損なわれています。ヒトでの把握反射が出生時に存在し、約5消える - 6ヶ月。しかし、このような誇張された速度や強度把握、把握するのに失敗、または把持反射の再来として把握反射の変化、年齢の6ヶ月後に、すべてのは、神経系への損傷を示しています。 CPモデルに把握比較するために、反射的把持赤字が決定しました。 損傷後48時間で、CPマウス（平均足把持反射を把握するの減少を実証します48時間で：CP 2.429±0.9376、N = 14、対3.214±0.8018偽、N = 14; P &lt;0.05、 図14A）。前肢の右肢の好みのわずかな、しかし有意ではない増加があった（データは示さず）。そこ後足の大幅な右足の好みだった（CP 75.0±42.74であり、n = 14、偽17.86±54.09対はn = 14; P &lt;0.005、 図14B）。 、特段の足の嗜好と;：一週間損傷後、CPマウス（P &lt;0.05、 図14C CP 2.75±1.035、N = 8を、対3.80±0.6325、N = 10を偽平均足は1週間で把握）の赤字を把握表示します。 <img alt="図14" src="/files/ftp_upload/53569/53569fig14.jpg" /> 図14. CPのマウスは、後足で、負傷脳領域に対側を把持赤字を持っています。 （A）48時間後の損傷（PND 8）、CPマウス（灰色のバー）、平均して、とスティックを把握、偽アニマよりも少ない足LS（黒いバー）。（B）CPマウス（灰色のバー）が、左後肢（損傷に同側）を使用してとは対照的に（損傷に対側）の右後足に把握するためのプリファレンスを表示します。シャムマウス（黒棒）は、この右足の好みは表示されません。右足の好みは次のように計算された（ - / [右足+左足+両足] * 100 [右足の足左]）を（C）一週間損傷後、CPマウス（灰色のバー）と比較して依然として赤字を把握示します。シャムス（黒いバー）。データは、平均±SEMとして表されます。 * P &lt;0.05、**は、p &lt;0.005である。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53569/53569fig14large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> CPのマウスは、クリフ嫌悪中にエッジから離れ向けます 崖回避テストは、阿波を回すために、マウスの固有の恐怖に依存しています安全性に向かって急な崖と頭からyの。いくつかのCP患者は前庭困難だけでなく、障害者のモータ制御を持っていますが、CPのマウスは、このテスト上の任意の障害を示しませんでした。

Watch this Scientific Journal Video about A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy at JoVE.com

A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy

Presented is a concise battery of mouse neonatal motor tests. Using these tests, neonatal motor deficits can be demonstrated in a variety of neonatal motor disorders. By having a standardized set of tests, results from different studies can be compared, allowing for better and accurate reporting between groups.

脳性麻痺の新生児マウスモデルにおける運動テストのバッテリー

As the sheer number of transgenic mice strains grow and rodent models of pediatric disease increase, there is an expanding need for a comprehensive, ...

a-battery-of-motor-tests-in-a-neonatal-mouse-model-of-cerebral-palsy

Nanyang Technological University

Research

JoVE Journal

Medicine

24.0K ビュー.  Lewiz Katz School of Medicine at Temple University. Presented is a concise battery of mouse neonatal motor tests. Using these tests, neonatal motor deficits can be demonstrated in a variety of neonatal motor disorders. By having a standardized set of tests, results from different studies can be compared, allowing for better and accurate reporting between groups.

ビデオ: A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy

Making Sense of Listening: The IMAP Test Battery

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the abilities to extract and use the information encoded in the auditory signal. We refer to these as listening skills (or auditory processing AP). Deficits in these skills are associated with delayed language and literacy development, though the nature of the relevant deficits and their causal connection with these delays is hotly debated.
When a child is referred to a health professional with normal hearing and unexplained difficulties in listening, or associated delays in language or literacy development, they should ideally be assessed with a combination of psychoacoustic (AP) tests, suitable for children and for use in a clinic, together with cognitive tests to measure attention, working memory, IQ, and language skills. Such a detailed examination needs to be relatively short and within the technical capability of any suitably qualified professional. Current tests for the presence of AP deficits tend to be poorly constructed and inadequately validated within the normal population. They have little or no reference to the presenting symptoms of the child, and typically include a linguistic component. Poor performance may thus reflect problems with language rather than with AP. To assist in the assessment of children with listening difficulties, pediatric audiologists need a single, standardized child-appropriate test battery based on the use of language-free stimuli.
We present the IMAP test battery which was developed at the MRC Institute of Hearing Research to supplement tests currently used to investigate cases of suspected AP deficits. IMAP assesses a range of relevant auditory and cognitive skills and takes about one hour to complete. It has been standardized in 1500 normally-hearing children from across the UK, aged 6-11 years. Since its development, it has been successfully used in a number of large scale studies both in the UK and the USA. IMAP provides measures for separating out sensory from cognitive contributions to hearing. It further limits confounds due to procedural effects by presenting tests in a child-friendly game-format. Stimulus-generation, management of test protocols and control of test presentation is mediated by the IHR-STAR software platform. This provides a standardized methodology for a range of applications and ensures replicable procedures across testers. IHR-STAR provides a flexible, user-programmable environment that currently has additional applications for hearing screening, mapping cochlear implant electrodes, and academic research or teaching.

A test battery (IMAP) for performing an in-depth assessment of auditory and cognitive abilities contributing to listening skills is described. It is quick to administer, child-friendly and free from linguistic confounds. Stimulus generation and protocol management are controlled via a software platform (IHR-STAR) to ensure replicable procedures.

IMAPのテストバッテリー：リスニングの意味を理解する

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the ...

医学

Mouse Model of Middle Cerebral Artery Occlusion

Stroke is the most common fatal neurological disease in the United States 1. The majority of strokes (88%) result from blockage of blood vessels in the brain (ischemic stroke) 2. Since most ischemic strokes (~80%) occur in the territory of middle cerebral artery (MCA) 3, many animal stroke models that have been developed have focused on this artery. The intraluminal monofilament model of middle cerebral artery occlusion (MCAO) involves the insertion of a surgical filament into the external carotid artery and threading it forward into the internal carotid artery (ICA) until the tip occludes the origin of the MCA, resulting in a cessation of blood flow and subsequent brain infarction in the MCA territory 4. The technique can be used to model permanent or transient occlusion 5. If the suture is removed after a certain interval (30 min, 1 h, or 2 h), reperfusion is achieved (transient MCAO); if the filament is left in place (24 h) the procedure is suitable as a model of permanent MCAO. This technique does not require craniectomy, a neurosurgical procedure to remove a portion of skull, which may affect intracranial pressure and temperature 6. It has become the most frequently used method to mimic permanent and transient focal cerebral ischemia in rats and mice 7,8. To evaluate the extent of cerebral infarction, we stain brain slices with 2,3,5-triphenyltetrazolium chloride (TTC) to identify ischemic brain tissue 9. In this video, we demonstrate the MCAO method and the determination of infarct size by TTC staining.

We demonstrate in the video a method for producing a middle cerebral artery occlusion in adult mice using an intraluminal monofilament. We also show how to evaluate the extent of cerebral infarction by 2,3,5-triphenyltetrazolium chloride (TTC) staining.

中大脳動脈閉塞のマウスモデル

Stroke is the most common fatal neurological disease in the United States 1. The majority of strokes (88%) result from blockage of blood vessels in the ...

Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient management strategies. Orthotopic mouse models of oral cancer have been developed to facilitate the study of factors that impact invasion and serve as model system for evaluating anti-tumor therapeutics. In these systems, visualization of disseminated tumor cells within oral cavity tissues has typically been conducted by either conventional histology or with in vivo bioluminescent methods. A primary drawback of these techniques is the inherent inability to accurately visualize and quantify early tumor cell invasion arising from the primary site in three dimensions. Here we describe a protocol that combines an established model for squamous cell carcinoma of the tongue (SCOT) with two-photon imaging to allow multi-vectorial visualization of lingual tumor spread. The OSC-19 head and neck tumor cell line was stably engineered to express the F-actin binding peptide LifeAct fused to the mCherry fluorescent protein (LifeAct-mCherry). Fox1nu/nu mice injected with these cells reliably form tumors that allow the tongue to be visualized by ex-vivo application of two-photon microscopy. This technique allows for the orthotopic visualization of the tumor mass and locally invading cells in excised tongues without disruption of the regional tumor microenvironment. In addition, this system allows for the quantification of tumor cell invasion by calculating distances that invaded cells move from the primary tumor site. Overall this procedure provides an enhanced model system for analyzing factors that contribute to SCOT invasion and therapeutic treatments tailored to prevent local invasion and distant metastatic spread. This method also has the potential to be ultimately combined with other imaging modalities in an in vivo setting.

A comprehensive overview of the techniques involved in generating a mouse model of oral cancer and quantitative monitoring of tumor invasion within the tongue through multi-photon microscopy of labeled cells is presented. This system can serve as a useful platform for the molecular assessment and drug efficacy of anti-invasive compounds.

口腔扁平上皮癌の同所性マウスモデルにおける腫瘍細胞の浸潤の多光子イメージング

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient ...

A Swine Model of Neonatal Asphyxia

Annually more than 1 million neonates die worldwide as related to asphyxia. Asphyxiated neonates commonly have multi-organ failure including hypotension, perfusion deficit, hypoxic-ischemic encephalopathy, pulmonary hypertension, vasculopathic enterocolitis, renal failure and thrombo-embolic complications. Animal models are developed to help us understand the patho-physiology and pharmacology of neonatal asphyxia. In comparison to rodents and newborn lambs, the newborn piglet has been proven to be a valuable model. The newborn piglet has several advantages including similar development as that of 36-38 weeks human fetus with comparable body systems, large body size (&tilde;1.5-2 kg at birth) that allows the instrumentation and monitoring of the animal and controls the confounding variables of hypoxia and hemodynamic derangements.
We here describe an experimental protocol to simulate neonatal asphyxia and allow us to examine the systemic and regional hemodynamic changes during the asphyxiating and reoxygenation process as well as the respective effects of interventions. Further, the model has the advantage of studying multi-organ failure or dysfunction simultaneously and the interaction with various body systems. The experimental model is a non-survival procedure that involves the surgical instrumentation of newborn piglets (1-3 day-old and 1.5-2.5 kg weight, mixed breed) to allow the establishment of mechanical ventilation, vascular (arterial and central venous) access and the placement of catheters and flow probes (Transonic Inc.) for the continuously monitoring of intra-vascular pressure and blood flow across different arteries including main pulmonary, common carotid, superior mesenteric and left renal arteries. Using these surgically instrumented piglets, after stabilization for 30-60 minutes as defined by Z&lt;10% variation in hemodynamic parameters and normal blood gases, we commence an experimental protocol of severe hypoxemia which is induced via normocapnic alveolar hypoxia. The piglet is ventilated with 10-15% oxygen by increasing the inhaled concentration of nitrogen gas for 2h, aiming for arterial oxygen saturations of 30-40%. This degree of hypoxemia will produce clinical asphyxia with severe metabolic acidosis, systemic hypotension and cardiogenic shock with hypoperfusion to vital organs. The hypoxia is followed by reoxygenation with 100% oxygen for 0.5h and then 21% oxygen for 3.5h. Pharmacologic interventions can be introduced in due course and their effects investigated in a blinded, block-randomized fashion.

Large animal models have good translational values in the examination of physiology and pharmacology of neonatal asphyxia. Using newborn piglets, we develop an experimental protocol to simulate neonatal asphyxia which has advantages of studying the systemic and regional hemodynamics, oxygen transport with biochemical and pathologic pathways and correlations.

新生児仮死の新型モデル

Annually more than 1 million neonates die worldwide as related to asphyxia. Asphyxiated neonates commonly have multi-organ failure including hypotension, ...

Non-invasive Optical Measurement of Cerebral Metabolism and Hemodynamics in Infants

Perinatal brain injury remains a significant cause of infant mortality and morbidity, but there is not yet an effective bedside tool that can accurately screen for brain injury, monitor injury evolution, or assess response to therapy. The energy used by neurons is derived largely from tissue oxidative metabolism, and neural hyperactivity and cell death are reflected by corresponding changes in cerebral oxygen metabolism (CMRO2). Thus, measures of CMRO2 are reflective of neuronal viability and provide critical diagnostic information, making CMRO2 an ideal target for bedside measurement of brain health.
Brain-imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) yield measures of cerebral glucose and oxygen metabolism, but these techniques require the administration of radionucleotides, so they are used in only the most acute cases.
Continuous-wave near-infrared spectroscopy (CWNIRS) provides non-invasive and non-ionizing radiation measures of hemoglobin oxygen saturation (SO2) as a surrogate for cerebral oxygen consumption. However, SO2 is less than ideal as a surrogate for cerebral oxygen metabolism as it is influenced by both oxygen delivery and consumption. Furthermore, measurements of SO2 are not sensitive enough to detect brain injury hours after the insult 1,2, because oxygen consumption and delivery reach equilibrium after acute transients 3. We investigated the possibility of using more sophisticated NIRS optical methods to quantify cerebral oxygen metabolism at the bedside in healthy and brain-injured newborns. More specifically, we combined the frequency-domain NIRS (FDNIRS) measure of SO2 with the diffuse correlation spectroscopy (DCS) measure of blood flow index (CBFi) to yield an index of CMRO2 (CMRO2i) 4,5.
With the combined FDNIRS/DCS system we are able to quantify cerebral metabolism and hemodynamics. This represents an improvement over CWNIRS for detecting brain health, brain development, and response to therapy in neonates. Moreover, this method adheres to all neonatal intensive care unit (NICU) policies on infection control and institutional policies on laser safety. Future work will seek to integrate the two instruments to reduce acquisition time at the bedside and to implement real-time feedback on data quality to reduce the rate of data rejection.

We combined frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation with diffuse correlation spectroscopy measures of cerebral blood flow index to estimate an index of oxygen metabolism. We tested the utility of this measure as a bedside screening tool to evaluate the health and development of the newborn brain.

乳幼児の脳代謝と血行動態の非侵襲的光計測

Perinatal brain injury remains a significant cause of infant mortality  and morbidity, but there is not yet an effective bedside tool that can  accurately ...

A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy

Birth asphyxia, which causes hypoxic-ischemic encephalopathy (HIE), accounts for 0.66 million deaths worldwide each year, about a quarter of the world&#8217;s 2.9 million neonatal deaths. Animal models of HIE have contributed to the understanding of the pathophysiology in HIE, and have highlighted the dynamic process that occur in brain injury due to perinatal asphyxia. Thus, animal studies have suggested a time-window for post-insult treatment strategies. Hypothermia has been tested as a treatment for HIE in pdiglet models and subsequently proven effective in clinical trials. Variations of the model have been applied in the study of adjunctive neuroprotective methods and piglet studies of xenon and melatonin have led to clinical phase I and II trials1,2. The piglet HIE model is further used for neonatal resuscitation- and hemodynamic studies as well as in investigations of cerebral hypoxia on a cellular level. However, it is a technically challenging model and variations in the protocol may result in either too mild or too severe brain injury. In this article, we demonstrate the technical procedures necessary for establishing a stable piglet model of neonatal HIE. First, the newborn piglet (&#60; 24 hr old, median weight 1500 g) is anesthetized, intubated, and monitored in a setup comparable to that found in a neonatal intensive care unit. Global hypoxia-ischemia is induced by lowering the inspiratory oxygen fraction to achieve global hypoxia, ischemia through hypotension and a flat trace amplitude integrated EEG (aEEG) indicative of cerebral hypoxia. Survival is promoted by adjusting oxygenation according to the aEEG response and blood pressure. Brain injury is quantified by histopathology and magnetic resonance imaging after 72 hr.

Hypoxic-ischemic encephalopathy following perinatal asphyxia can be studied using animal models. We demonstrate the procedures necessary for establishing a piglet model of neonatal hypoxic-ischemic encephalopathy.

新生児低酸素性虚血性脳症の子豚モデル

Birth asphyxia, which causes hypoxic-ischemic encephalopathy (HIE), accounts for 0.66 million deaths worldwide each year, about a quarter of the ...

Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a lifetime prevalence of 14% and is the most common urological diagnosis for men under the age of 50, yet it is the least understood and studied chronic pelvic pain disorder. A significant subset of patients with chronic pelvic pain report having experienced early life stress or abuse, which can markedly affect the functioning and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mast cell activation, which has been shown to be increased in both urine and expressed prostatic secretions of CP/CPPS patients, is partially regulated by downstream activation of the HPA axis. Neonatal maternal separation (NMS) has been used for over two decades to study the outcomes of early life stress in rodent models, including changes in the HPA axis and visceral sensitivity. Here we provide a detailed protocol for using NMS as a preclinical model of CP/CPPS in male C57BL/6 mice. We describe the methodology for performing NMS, assessing perigenital mechanical allodynia, and histological evidence of mast cell activation. We also provide evidence that early psychological stress can have long-lasting effects on the male urogenital system in mice.

We are measuring perigenital mechanical sensitivity and mast cell activation in the prostate of male C57BL/6 mice that underwent an early life stress paradigm &#8211; neonatal maternal separation, in order to induce a preclinical model of chronic prostatitis/chronic pelvic pain syndrome.

新生児母子分離のマウスモデルにおけるPerigenital感度と前立腺肥満細胞の活性化の評価

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a lifetime prevalence of 14% and is the most common urological diagnosis for men under the ...

A Neonatal Mouse Spinal Cord Compression Injury Model

Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life1, this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques1. Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections1.

This article describes a method for generating a reproducible spinal cord compression injury (SCI) in the neonatal mouse. The model provides an advantageous platform for studying mechanisms of adaptive plasticity that underlie spontaneous functional recovery.

新生児マウス脊髄圧縮損傷モデル

Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal ...

Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration

Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and regeneration, and to define new targets for therapeutics. For decades, models of complete heart regeneration existed in amphibians and fish, but a mammalian counterpart was not available. The recent discovery of a postnatal window during which mice possess regenerative capabilities has led to the establishment of a mammalian model of cardiac regeneration. A surgical model of mammalian cardiac regeneration in the neonatal mouse is presented herein. Briefly, postnatal day 1 (P1) mice are anesthetized by isoflurane and placed on an ice pad to induce hypothermia. After the chest is opened, and the left anterior descending coronary artery (LAD) is visualized, a suture is placed around the LAD to inflict myocardial ischemia in the left ventricle. The surgical procedure takes 10-15 min. Visualizing the coronary artery is crucial for accurate suture placement and reproducibility. Myocardial infarction and cardiac dysfunction are confirmed by triphenyl-tetrazolium chloride (TTC) staining and echocardiography, respectively. Complete regeneration 21 days post myocardial infarction is verified by histology. This protocol can be used to as a tool to elucidate mechanisms of mammalian cardiac regeneration after myocardial infarction.

This protocol describes a highly reproducible model of cardiac regeneration by surgical induction of myocardial infarction in the left ventricle of postnatal day 1 mice. The method involves induction of hypothermic anesthesia and ligation of the left anterior descending coronary artery.

新生児マウスの心筋梗塞、心臓再生のモデル

Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and ...

Transient Middle Cerebral Artery Occlusion Model of Neonatal Stroke in P10 Rats

A number of animal models have been used to study hypoxic-ischemic injury, traumatic injury, global hypoxia, or permanent ischemia in both the immature and mature brain. Stroke occurs commonly in the perinatal period in humans, and transient ischemia-reperfusion is the most common form of stroke in neonates. The reperfusion phase is a critical component of injury progression, which occurs over a period of days to weeks, and of the endogenous response to injury. This postnatal day 10 (p10) rat model of transient middle cerebral artery occlusion (tMCAO) creates a unilateral, non-hemorrhagic focal ischemia-reperfusion injury that can be utilized to study the mechanisms of focal injury and repair in the full-term-equivalent brain. The injury pattern that is produced by tMCAO is consistent and highly reproducible and can be confirmed with MRI or histological analyses. The severity of injury can be manipulated through changes in occlusion time and other methods that will be discussed.

Neonatal stroke is a significant cause of early brain injury requiring a translational model with consistent focal injury patterns and high reproducibility in order to enable study. This study describes the detailed surgical procedure for creating a non-hemorrhagic, unilateral focal ischemia-reperfusion injury in full-term-equivalent rodents.

P10ラットにおける新生児脳卒中の一過性中大脳動脈閉塞モデル

A number of animal models have been used to study hypoxic-ischemic injury, traumatic injury, global hypoxia, or permanent ischemia in both the immature ...