Intrathecal drug delivery is routinely used in the treatment and prophylaxis of varied central nervous system conditions, as doing so allows drugs to directly bypass the blood-brain barrier. However, the utility of this route of administration is limited by poor brain and spinal cord parenchymal drug uptake from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol can significantly increase influx of cerebrospinal fluid into the perivascular spaces of the brain, to enhance the uptake of intrathecally administered drugs. Specifically, we administered small (~1 kDa) and large (~155 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of small molecule agents into the brain parenchyma, and of both small and large molecule agents into the perivascular space from the cerebrospinal fluid. Notably, there was no evidence of brain parenchymal damage following this intervention. The low intensity and noninvasive approach of transcranial ultrasound in this protocol underscores the ready path to clinical translation of this technique. In this manner, this protocol can be used to directly bypass the blood-brain barrier for whole-brain delivery of a variety of agents. Additionally, this technique can potentially be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated.

鞘内给药通常用于治疗和预防各种中枢神经系统疾病，因为这样做可以使药物直接绕过血脑屏障。然而，这种给药途径的效用受到脑和脊髓实质药物从脑脊液中吸收不良的限制。我们证明了一个简单的无创经颅超声方案可以显着增加脑脊液流入大脑血管周围空间，从而增强鞘内给药的药物的吸收。具体来说，我们将小 (~1 kDa) 和大 (~155 kDa) 分子药物注入大鼠的大脑池，然后在整个大脑的扫描方案中应用低诊断强度聚焦超声。使用实时磁共振成像和在体外组织学分析中，我们观察到小分子药物进入脑实质的摄取显着增加，以及从脑脊液进入血管周围空间的小分子和大分子药物的摄取显着增加。值得注意的是，没有证据表明这种干预后脑实质受损。该协议中经颅超声的低强度和无创方法强调了该技术临床转化的现成途径。通过这种方式，该协议可用于直接绕过血脑屏障，用于各种药剂的全脑递送。此外，这种技术可以潜在地用作探索类淋巴系统在与其相关的各种疾病和生理过程中的因果作用的一种手段。