Time-reversal Techniques in Ultrasound-assisted Convection-enhanced Drug Delivery to the Brain: Technology Development and In Vivo Evaluation.

We describe a drug delivery method that combines Time-Reversal Acoustics (TRA) with Convection-Enhanced Delivery (CED) to improve the delivery of therapeutics to the interstitium of the brain. The Ultrasound-assisted CED approach (UCED) circumvents the blood-brain barrier by infusing compounds through a cannula that is inserted into the brain while simultaneously delivering ultrasound to improve the penetration of pharmaceuticals. CED without ultrasound-assistance has been used to treat a variety of neural disorders, including glioblastoma multiforme, a malignancy that presents a very poor prognosis for patients. We describe a novel system that is used to infuse fluids into the brain parenchyma while simultaneously exposing the tissue to safe levels of 1-MHz, low intensity, ultrasound energy. The system includes a combined infusion needle-hydrophone, a 10-channel ultralow-output impedance amplifier, a broad-band ultrasound resonator, and MatLab®-based TRA control and user-interface. TRA allows easy coupling of ultrasound therapy through the skull without complex phase-correction and array design. The smart targeting UCED system has been tested in vivo and results show it provides 1.5-mm spatial resolution for UCED and improves tracer distribution in the brain over CED alone.

Memory for reward location is enhanced even though acetylcholine efflux within the amygdala is impaired in rats with damage to the diencephalon produced by thiamine deficiency.

A rodent model of diencephalic amnesia produced by thiamine deficiency (pyrithiamine-induced thiamine deficiency [PTD]) was implemented to assess both changes in behavior and acetylcholine (ACh) efflux in the amygdala across four training sessions of a delayed alternation task. Two versions of the delayed alternation task were used. In one version, when a correct alternation was made a unique reward was paired with each spatial location ([left arm-chocolate milk] or [right arm-rat chow]). This paradigm is called the differential outcomes procedure (DOP). In the second version of the task, correct delayed alternation resulted in the same rewards but randomized across location (Nondifferential Outcomes Procedure [NOP]). The PTD rats were impaired on the first session of delayed alternation testing. However, both control and PTD rats using the DOP performed significantly better on delayed alternation than rats trained with the NOP.This effect was driven primarily by the PTD rats in the DOP condition outperforming all other groups on sessions 2-4. Although ACh efflux in the amygdala increased during delayed alternation testing in all groups, the NOP-trained rats had a greater rise in training-related ACh release in the post-training period. This suggests that increased amygdalar cholinergic activation is more critical for processing spatial information than episodic reward information. These data correspond with the idea that cholinergic activation of the amygdala promotes processing in other neural systems.