Dr. Antoniades was supported by the National Institute of Health Research (NIHR) and by the Dementias and Neurodegenerative Diseases Research Network (DENDRON) and by the Wellcome Trust. Dr FitzGerald was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.

地元の倫理委員会は、セクション1で以下に詳述するように、参加者から得た同意、この研究を承認したと伝えました。 1.参加者の同意<ol><li>テストセッションが含まれるかを詳細に説明して情報シートを持つ参加者を提供します。 </li><li>参加者は同意書上の各点を説明し、それらに任意の質問をする機会を与え、彼らと同意書を通過し、読み、研究では、それらの撮影部分に関連したご質問、懸念や他の問題を議論する機会を持った後、彼らが持っているかもしれません。フォームを完了するために、参加者を確認して下さい。 </li></ol> 2. Saccadometerを設定します<ol><li>患者の頭部上のデバイス、調節可能な弾性ストラップで固定さと鼻の橋の上に載っを置きます。刺激が頭を正確に移動するので、全く頭拘束は必要ありません、デバイスはWEAに快適ですrを。 </li><li>フラットマットスクリーンから1.5メートルに座って患者を確認して下さい。 </li><li>刺激（赤色光スポットが）明確に見られるように、周囲の照明が暗いことを確認してください。 </li></ol>サッカードセッションのレコーディング3. 注：例としてprosaccadesとantisaccades 8の両方をテストし、標準的なプロトコルはここで説明されています。 60 prosaccades、40 antisaccades×3、およびブロック間の1分の休憩で60 prosaccades：このプロトコルは、5つのブロックで構成されています。セッションは約40分続きます。 <ol><li>それが消滅し、ペリフェラルターゲットのいずれかがランダムに9右または左に、表示された後2.0秒、 -各試験のために中央の固視標が1.0のランダムフォア期間表示されるようにsaccadometerを設定します。 注：3つのターゲットは、参加者の前でスクリーンに投影赤色光のスポットである（2.2参照）saccadometerに組み込ま低出力レーザーによって。 saccadometerのAUTomaticallyディスプレイにオンとオフのレーザーを切り替え/必要な配列内のターゲットを消します。 </li><li>テストはブロック間の1分間の休憩を持つ5つのブロックで構成され、参加者に指示します。 </li><li>前最初のブロックに片側または他に途中から飛び降り赤い点に従うと、この60回を行うためにそれらを指示するために可能な限り迅速かつ正確に彼らの目を移動するために、参加者に指示します。 </li><li> 60試験のシーケンスを生成するためにsaccadometerを設定します。トライアル（prosaccades）の最初のブロックを開始するためにsaccadometerのボタンを押してください。 </li><li>第1のブロックの終了後、第二のブロックの前に1分間のギャップを残します。 40試験のシーケンスを生成するためにsaccadometerをリセットし、1分間隔の終わりに向かって、赤い点と反対方向に可能な限り迅速に彼らの目を移動するために次のブロックのための参加者に指示し、彼らがすることを説明この40倍を行うために必要とされます。秒を開始トライアル（antisaccades）の二のブロック。 </li><li>第二のブロックの終了後、ステップ3.5で命令を繰り返し、試験（antisaccades）の第3のブロックを開始し、さらに1分間のギャップを残します。 </li><li>第3ブロックの終了後、ステップ3.5で命令を繰り返し、試験（antisaccades）の第4ブロックを開始し、さらに1分間のギャップを残します。 </li><li>第4ブロックの終了後、さらに1分のギャップを残して、テストの最後のブロックのために片側またはに途中から飛び降り赤い点を追従するように迅速かつ正確に可能な限り彼らの目を移動するために、参加者に求めることを説明彼らは最初のブロックでまったく同じように、他の。 </li><li> 60試験のシーケンスを生成し、試験（prosaccades）の最後のブロックを開始するsaccadometerをリセットします。 </li></ol><img alt="図2" src="/files/ftp_upload/53640/53640fig2.jpg" /> 図2.眼球運動の作業。回路図illustratiサッカードのタスクの2つの例を示した上で。固体青色のスポットは、ターゲットを表し、点線の青い円は、固定の領域を表します。LEFTは、被験者がターゲットに目を向けるように指示されるprosaccadicタスクを示している。RIGHT被験者が視覚刺激から目をそらすように頼まれる抗サッケードを示しています。これは、反対方向にサッカードのより自然なprosaccade応答および生成の阻害を必要とする。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53640/53640fig2large.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> 4.脳​​深部刺激の設定注：脳深部刺激剤と参加者が刺激システムは、 すなわち 、通常どおりに動作していると、これまでテストを実施するために、「刺激に」データセットが得られています。試験は、現在（オフ刺激システムで繰り返される必要がありますDBSシステムのない健常対照者については、このセクションでは）適用されません。 <ol><li> DBSシステムのスイッチをオフにします。訓練を受けた臨床スタッフによってこれを行います。試験前に30分を許可します。 </li><li>完全な「刺激オフ」データセットを得るために - 衝動性のテストを繰り返して（3.9 3.2ステップ）。 </li><li>バック（再び、これは適切な訓練を受けた医療スタッフによって行われるべきである）上のDBSシステムを切り替えます。 </li></ol> 5.データ解析注：脳深部刺激剤と参加者が刺激システムは、 すなわち 、通常どおりに動作していると、これまでテストを実施するために、「刺激に」データセットが得られています。テストは今刺激システムで繰り返される必要がある（このセクションは適用されませんDBSシステムなしで健常対照者のために）オフ。 <ol><li>分析のためにコンピュータにsaccadometerからの生データをダウンロードしてください。 </li><li>サッカードを除外するためにsaccadometerのソフトウェアプログラムを使用しdistor点滅し、頭の動きによりテッド、そしてサッカード潜時、ピーク速度、および振幅などの変数を計算します。 注意：過度の頭の動きや点滅によって汚染されたレコードは、ソフトウェアによって自動的に削除されます。 <ol><li> 80ミリ秒または千ミリ秒より大きい未満のレイテンシでサッカードを削除してください。 注：サッカード待ち時間は、速度および加速度に基づいて、サッケード検出アルゴリズムを用いて自動的に計算されます。サッケードの開始は眼速度が5度/秒の閾値を超えた時点として特定されます。 </li></ol></li></ol>

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</ol>

The authors have nothing to disclose.

良質衝動性データを得るための最も重要な要因は、参加者に与えられた指示は明確かつ正確であることを保証することです。 antisaccadic作業の指示が完全に明らかにされていない場合たとえば、参加者が代わりにprosaccadesを実行する可能性があります。参加者が明らかに刺激またはsaccadometerが正確に目の位置を測定することはできません見ることができない場合は録画も台無しにすることがで?...

近年1を作る神経決定の高レベルのメカニズムに関する情報を得るの定量的および非侵襲的な方法として、反応時間の測定の使用に関心が高まっています。広く研究されてきた反応時間の一つのタイプは、サッケード待ち時間として知られている、視覚刺激の提示にサッカードを開始するのに要する時間です。サッカードは、我々は急速にある場所から別の場所に私たちの視線を移すときに発生する高速な眼球運動です。彼らは典型的には、2つまたは毎秒3の頻度で発生した、私たちが作る眼球運動の最も一般的なタイプです。各サッカードが有効で、別の2のではなく、視覚的な世界では1のキューを見て決定です。 目の動きを制御する神経経路は広く研究されており、かなりよく3を文書化されています。敏感な電子機器を使用して、眼球運動機能の側面を正確かつobjectivelすることができyは定量化。これは、眼球運動そのものの詳細な研究を促進するだけでなく、神経生理学や病態生理の他の領域を調査するためのツールと​​して使用するためにそれらを可能にします。 眼球運動の測定は、疾患状態についての有用な情報を提供することができます。眼球運動は、最近、例えば、ハンチントン4,5およびパーキンソン病6,7を含む神経変性疾患の潜在的なバイオマーカーとして注目されており、十分にサッケード反応時間は、これらの条件下で通常よりも遅くなる傾向があることが確立されています。サッカード測定の潜在的な用途は、診断や病気の追跡への補助があります。サッカードのタスクは、単純なprosaccade（左または右に突然現れた視覚刺激に向かって可能な限り迅速に探している）から、このような抗サッケード（視覚刺激とは反対側に、可能な限り迅速に探して）、またはメモリ - など、より複雑な作業の範囲導かれたサッカード（探し）はもはや存在しないターゲットの思い出した場所に向かって。 脳深部刺激は、いくつかの神経疾患に対する有効な治療法です。最も一般的振戦、硬直、運動緩慢、およびジスキネジアを含むパーキンソン病の運動症状を治療するために使用されます。また、そのような強迫性障害などのあまり一般的ではないが、神経因性疼痛、てんかん、および精神医学的状態のためのジストニアと本態性振戦、およびを含む他の運動障害のために使用されます。これは、科学者は、生体内で人間の脳の深部構造への直接の電気的アクセスを持っているので、実験的な神経学のための貴重な機会を提供する唯一の設定です。種々の標的は、動眼神経経路に関与しているそれらの多くは大脳基底核内のいくつかの場所、を含む、治療される状態に応じて刺激されます。これは、研究の広い範囲は、刺激を送達するためにDBSシステムを用いて行うことができることを意味します与えられた脳位置およびアイトラッキング装置に記録し、その効果を分析します。実験パラダイムによって、このような研究は、疾患、またはDBSは、その特定の設定で作動される機構の効果を刺激される領域の生理機能についての情報を得ることができます。この記事では、脳深部刺激患者における衝動性眼球運動試験の一般的なアプローチについて説明します。 アイトラッキング装置のいくつかの異なる種類があります。このプロトコールに記載された研究のためにポータブルsaccadometer水平衝動性眼球運動を記録するために使用されました。ポータブルsaccadometersはセッションが特に厳しいジスキネジアで苦しむ人々のために、パーキンソン病の患者にとってより快適であることを意味する（ 図1参照 ）ヘッドレストを必要としないという利点を有します。ここで使用saccadometerは、軽量で約5センチ幅10センチです。 saccadometerのmeasu直接赤外線眼球運動記録法の使用による解像度の眼球運動：内側眼角の使用光の前方に位置する赤外線源とセンサは、ミリ秒間隔で眼球の回転位置を確立するために、角膜からの反射しました。分析のための良質のデータを取得するためにsaccadometerは、少なくとも12ビットの分解能を有する少なくとも1 kHzの速度でサンプリングする必要があります。ここで使用saccadometerでは視覚刺激は、によって生成された光の3赤13のcdメートル-2スポットがあった低出力レーザーに建てられ、1正中線のスポットと±10度で、他の2といくつかの0.1度を従属各スポット（ すなわち 、 、）右と左に。 <img alt="図1" src="/files/ftp_upload/53640/53640fig1.jpg" /> 図1. Saccadometer。ヘッドsaccadometer弾性バンドに取り付けられ、鼻の橋の上に載って取り付けられました。四つのミニチュアレーザープロジェクト視標マット面上への、そして参加者の目の動きは、各眼の鼻側の差動赤外線反射率変換器によって測定されます。レーザーターゲットが頭を動かすと、ヘッドレストは必要ありません。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53640/53640fig1large.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>

<table><tbody><tr><td>Saccadometer device</td><td>Ober Consulting Poland</td><td></td><td></td></tr><tr><td>Computer with Windows environment</td><td></td><td></td><td></td></tr><tr><td>Software, Latency Meter for downloading the raw data from the saccadometer</td><td></td><td></td><td></td></tr></tbody></table>

using saccadometry with deep brain stimulation to study normal and pathological brain function

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including Parkinson's and Huntington's can disrupt it. People with Parkinson's disease, for example, tend to have increased saccadic latencies. Consequently, the quantitative measurement of saccadic eye movements has received considerable attention as a potential biomarker for neurodegenerative conditions. A lot more can be learned about the brain in both health and disease by observing what happens to eye movements when the function of specific brain areas is perturbed. Deep brain stimulation is a surgical intervention used for the management of a range of neurological conditions including Parkinson's disease, in which stimulating electrodes are placed in specific brain areas including several sites in the basal ganglia. Eye movement measurements can then be made with the stimulator systems both off and on and the results compared. With suitable experimental design, this approach can be used to study the pathophysiology of the disease being treated, the mechanism by which DBS exerts it beneficial effects, and even aspects of normal neurophysiology.

図3は、移植視床下核DBSシステムとパーキンソン病患者から、衝動性眼球運動の軌跡の一例を示す図です。刺激システムがオフ（上のグラフ）と（下のグラフ）に切り替えて二つのグラフは、患者のprosaccadesをプロットします。グラフ上の各トレースは度で目の位置が離れて正中線（y軸）からの時間（x軸）の関数として変化する、すなわち、どの?...

Watch this Scientific Journal Video about Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function at JoVE.com

Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function

This paper describes the use of quantitative measurement of eye movements in conjunction with stimulation of focal areas of the deep brain in order to study physiology, pathophysiology, and the mechanisms of deep brain stimulation.

正常および病的脳機能を研究するために脳深部刺激でSaccadometryを使用します

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including ...

using-saccadometry-with-deep-brain-stimulation-to-study-normal

Research

JoVE Journal

Medicine

7.4K ビュー.  The University of Oxford. This paper describes the use of quantitative measurement of eye movements in conjunction with stimulation of focal areas of the deep brain in order to study physiology, pathophysiology, and the mechanisms of deep brain stimulation.

ビデオ: Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor 1. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials 2. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. 
DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation 3. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity 4,5. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain. This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.

脳深部刺激術を受けた覚醒ヒトにおける術中行動作業

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through ...

医学

Combined Invasive Subcortical and Non-invasive Surface Neurophysiological Recordings for the Assessment of Cognitive and Emotional Functions in Humans

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging (fMRI) for extracting crucial information about the mechanism of the human brain, such methods remain insufficient to provide information about physiological processes reflecting cognitive and emotional functions at the subcortical level. In this respect, modern invasive clinical approaches in humans, such as deep brain stimulation (DBS), offer a tremendous possibility to record subcortical brain activity, namely local field potentials (LFPs) representing coherent activity of neural assemblies from localized basal ganglia or thalamic regions. Notwithstanding the fact that invasive approaches in humans are applied only after medical indication and thus recorded data correspond to altered brain circuits, valuable insight can be gained regarding the presence of intact brain functions in relation to brain oscillatory activity and the pathophysiology of disorders in response to experimental cognitive paradigms. In this direction, a growing number of DBS studies in patients with Parkinson&#39;s disease (PD) target not only motor functions but also higher level processes such as emotions, decision-making, attention, memory and sensory perception. Recent clinical trials also emphasize the role of DBS as an alternative treatment in neuropsychiatric disorders ranging from obsessive compulsive disorder (OCD) to chronic disorders of consciousness (DOC). Consequently, we focus on the use of combined invasive (LFP) and non-invasive (EEG) human brain recordings in assessing the role of cortical-subcortical structures in cognitive and emotional processing trough experimental paradigms (e.g. speech stimuli with emotional connotation or paradigms of cognitive control such as the Flanker task), for patients undergoing DBS treatment.

The present protocol aims at assessing cognitive-emotional functions in the basal ganglia by simultaneous neurophysiological recording of local field potentials and non-invasive brain cortical activity (EEG). The procedure is exemplified by the use of paradigms involving speech stimuli with emotional connotation or the Flanker task involving cognitive control.

認知の評価とヒトにおける感情的な関数の組み合わせ侵襲性皮質下および非侵襲性の面神経生理学レコーディング

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging ...

行動学

A Novel Approach to Assess Motor Outcome of Deep Brain Stimulation Effects in the Hemiparkinsonian Rat: Staircase and Cylinder Test

Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson&#39;s disease. In our lab we established a protocol to screen different neurostimulation patterns in hemiparkinsonian (unilateral lesioned) rats. It consists of creating a unilateral Parkinson&#39;s lesion by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, implanting chronic stimulation electrodes into the subthalamic nucleus and evaluating motor outcomes at the end of 24 hr periods of cable-bound external neurostimulation. The stimulation was conducted with constant current stimulation. The amplitude was set 20% below the individual threshold for side effects. The motor outcome evaluation was done by the assessment of spontaneous paw use in the cylinder test according to Shallert and by the assessment of skilled reaching in the staircase test according to Montoya. This protocol describes in detail the training in the staircase box, the cylinder test, as well as the use of both in hemiparkinsonian rats. The use of both tests is necessary, because the staircase test seems to be more sensitive for fine motor skill impairment and exhibits greater sensitivity to change during neurostimulation. The combination of the unilateral Parkinson model and the two behavioral tests allows the assessment of different stimulation parameters in a standardized way.

Deep brain stimulation (DBS) is an effective treatment option for Parkinson's disease. We established a study design to screen novel stimulation paradigms in rats. The protocol describes the use of the staircase test and cylinder test for motor outcome assessment in DBS treated hemiparkinsonian rats.

Hemiparkinsonianラットにおける脳深部刺激効果のモーターの成果を評価するための新しいアプローチ：階段室とシリンダーテスト

Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson&#39;s disease. In our lab we established a protocol to ...

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson&#39;s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.
Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson&#39;s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.

Adaptive deep brain stimulation (aDBS) is effective for Parkinson&#8217;s disease, improving symptoms and reducing power consumption compared to conventional deep brain stimulation (cDBS). In aDBS we track a local field potential biomarker (beta oscillatory amplitude) in real time and use this to control the timing of stimulation.

アダプティブ脳深部刺激とパーキンソン病の防除

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time ...

Deep Brain Stimulation with Simultaneous fMRI in Rodents

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to image rodents with simultaneous DBS. DBS fMRI presents a number of technical challenges, including accuracy of electrode implantation, MR artifacts created by the electrode, choice of anesthesia and paralytic to minimize any neuronal effects while simultaneously eliminating animal motion, and maintenance of physiological parameters, deviation from which can confound the BOLD signal.&#160;Our laboratory has developed a set of procedures that are capable of overcoming most of these possible issues. For electrical stimulation, a homemade tungsten bipolar microelectrode is used, inserted stereotactically at the stimulation site in the anesthetized subject. In preparation for imaging, rodents are fixed on a plastic headpiece and transferred to the magnet bore. For sedation and paralysis during scanning, a cocktail of dexmedetomidine and pancuronium is continuously infused, along with a minimal dose of isoflurane; this preparation minimizes the BOLD ceiling effect of volatile anesthetics. In this example experiment, stimulation of the subthalamic nucleus (STN) produces BOLD responses which are observed primarily in ipsilateral cortical regions, centered in motor cortex. Simultaneous DBS and fMRI allows the unambiguous modulation of neural circuits dependent on stimulation location and stimulation parameters, and permits observation of neuronal modulations free of regional bias. This technique may be used to explore the downstream effects of modulating neural circuitry at nearly any brain region, with implications for both experimental and clinical DBS.

This protocol describes a standard method for simultaneous functional magnetic resonance imaging and deep brain stimulation in the rodent. The combined use of these experimental tools allows for the exploration of global downstream activity in response to electrical stimulation at virtually any brain target.

げっ歯類での同時のfMRIと脳深部刺激

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for ...

神経科学

Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus

Deep brain stimulation (DBS) surgery, targeting various regions of the brain such as the basal ganglia, thalamus, and subthalamic regions, is an effective treatment for several movement disorders that have failed to respond to medication. Recent progress in the field of DBS surgery has begun to extend the application of this surgical technique to other conditions as diverse as morbid obesity, depression and obsessive compulsive disorder. Despite these expanding indications, little is known about the underlying physiological mechanisms that facilitate the beneficial effects of DBS surgery. One approach to this question is to perform gene expression analysis in neurons that receive the electrical stimulation. Previous studies have shown that neurogenesis in the rat dentate gyrus is elicited in DBS targeting of the anterior nucleus of the thalamus1. DBS surgery targeting the ATN is used widely for treatment refractory epilepsy. It is thus of much interest for us to explore the transcriptional changes induced by electrically stimulating the ATN. In this manuscript, we describe our methodologies for stereotactically-guided DBS surgery targeting the ATN in adult male Wistar rats. We also discuss the subsequent steps for tissue dissection, RNA isolation, cDNA preparation and quantitative RT-PCR for measuring gene expression changes. This method could be applied and modified for stimulating the basal ganglia and other regions of the brain commonly clinically targeted. The gene expression study described here assumes a candidate target gene approach for discovering molecular players that could be directing the mechanism for DBS.

The mechanism underlying the therapeutic effects of Deep Brain Stimulation (DBS) surgery needs investigation. The methods presented in this manuscript describe an experimental approach to examine the cellular events triggered by DBS by analyzing the gene expression profile of candidate genes that can facilitate neurogenesis post DBS surgery.

視床前核の脳深部刺激後のラット海馬における遺伝子発現の変化の解析

Deep brain stimulation (DBS) surgery, targeting various regions of the brain such as the basal ganglia, thalamus, and subthalamic regions, is an effective ...

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 M&#937; was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.

A method for implanting electrodes into the subthalamic nucleus (STN) of rats is described. Better localization of the STN was achieved by using a microrecording system. Furthermore, a stimulation set-up is presented that is characterized by long-lasting connections between the head of the animal and the stimulator.

微小電極は、長期的な脳深部刺激のためのラットの視床下核に電極の移植ガイド付き

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, ...

Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for movement disorders and is being applied to a growing number of disorders. Computational modeling has been successfully used to predict the clinical effects of DBS; however, there is a need for novel modeling techniques to keep pace with the growing complexity of DBS devices. These models also need to generate predictions quickly and accurately. The goal of this project is to develop an image processing pipeline to incorporate structural magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) into an interactive, patient specific model to simulate the effects of DBS. A virtual DBS lead can be placed inside of the patient model, along with active contacts and stimulation settings, where changes in lead position or orientation generate a new finite element mesh and solution of the bioelectric field problem in near real-time, a timespan of approximately 10 seconds. This system also enables the simulation of multiple leads in close proximity to allow for current steering by varying anodes and cathodes on different leads. The techniques presented in this paper reduce the burden of generating and using computational models while providing meaningful feedback about the effects of electrode position, electrode design, and stimulation configurations to researchers or clinicians who may not be modeling experts.

The goal of this project is to develop an interactive, patient-specific modeling pipeline to simulate the effects of deep brain stimulation in near real-time and provide meaningful feedback as to how these devices influence neural activity in the brain.

対話型、患者固有のモデルを用いた脳深部刺激療法の神経繊維の管を対象と

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for ...

生物工学

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

In this study, the methodology is presented on how to perform multi-site in vivo electrophysiological recordings from the hyperdirect pathway under urethane anesthesia.

急性<em&gt;インビボ</em&gt;麻酔ラットにおけるHyperdirect経路からの局所場ポテンシャルとマルチユニット活性の電気生理学的記録

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the ...

An Invasive Method for the Activation of the Mouse Dentate Gyrus by High-frequency Stimulation

Electrical high-frequency stimulation (HFS), using implanted electrodes targeting various brain regions, has been proven as an effective treatment for various neurological and psychiatric disorders. HFS in the deep region of the brain, also named deep-brain stimulation (DBS), is becoming increasingly important in clinical trials. Recent progress in the field of high-frequency DBS (HF-DBS) surgery has begun to spread the possibility of utilizing this invasive technique to other situations, such as treatment for major depression disorder (MDD), obsessive-compulsive disorder (OCD), and so on. 
Despite these expanding indications, the underlying mechanisms of the beneficial effects of HF-DBS remain enigmatic. To address this question, one approach is to use implanted electrodes that sparsely activate distributed subpopulations of neurons by HFS. It has been reported that HFS in the anterior nucleus of the thalamus could be used for the treatment of refractory epilepsy in the clinic. The underlying mechanisms might be related to the increased neurogenesis and altered neuronal activity. Therefore, we are interested in exploring the physiological alterations by the detection of neuronal activity as well as neurogenesis in the mouse dentate gyrus (DG) before and after HFS treatment. 
In this manuscript, we describe methodologies for HFS to target the activation of the DG in mice, directly or indirectly and in an acute or chronic manner. In addition, we describe a detailed protocol for the preparation of brain slices for c-fos and Notch1 immunofluorescent staining to monitor the neuronal activity and signaling activation and for bromodeoxyuridine (BrdU) labeling to determine the neurogenesis after the HF-DBS induction. The activation of the neuronal activity and neurogenesis after the HF-DBS treatment provides direct neurobiological evidence and potential therapeutic benefits. Particularly, this methodology can be modified and applied to target other interested brain regions such as the basal ganglia and subthalamic regions for specific brain disorders in the clinic.

This protocol shows how to set up a reliable HFS method in mice. Neurons throughout the hippocampal dentate gyrus are electrically stimulated by HFS directly and indirectly in vivo. Neuronal activity and molecular signaling are examined by c-fos and Notch1 immunofluorescent staining, respectively; neurogenesis is quantified by bromodeoxyuridine labeling assay.

高周波刺激によるマウスの海馬歯状回の活性化のための侵襲的な方法

Electrical high-frequency stimulation (HFS), using implanted electrodes targeting various brain regions, has been proven as an effective treatment for ...