Computer Algorithm May Improve Accuracy, Coverage of Drug Delivery to Brain

A new computer algorithm that guides intracerebral injections to improve drug delivery to the brain has been developed by researchers at the Massachusetts Institute of Technology.

The new technology, dubbed COMMAND (computational mapping algorithms for neural drug delivery), was designed to effectively deliver therapeutic molecules to specific brain structures, which has been a stumbling block in developing therapies for conditions such as Parkinson’s disease.

The approach was reported in a study, “Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices,” published in the peer-reviewed journal Cell Reports.

Diseases such as Parkinson’s arise from the dysfunction of specific brain structures. In the case of Parkinson’s, neurons of a region of the forebrain called the striatum — involved in voluntary movement control — are gradually lost, resulting in many of the condition’s symptoms.

Specifically targeting structures such as the striatum is a major therapeutic goal, challenged by both the blood-brain barrier — a semipermeable membrane that protects the brain and spinal cord — and the potential for side effects in regions not affected by a given disorder.

Current techniques to target specific brain regions include the use of an intracerebral catheter, as a means of injecting medication directly into a specific point of the brain. This has been used, for instance, to deliver glial-cell-derived neurotrophic factor (GDNF) as a therapy for Parkinson’s disease, since it is thought that GDNF supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and are progressively lost in Parkinson’s.

Despite promising preclinical studies, however, this technique has repeatedly failed to show great success in humans. The researchers believe that this failure may result from the single point of injection failing to adequately cover the target areas: the substantia nigra and the striatum.

“Accurate delivery of drugs to reach these targets is really important to ensure optimal efficacy and avoid off-target adverse effects,” Michael Cima, PhD, the study’s senior author, said in a press release. “Our new system, called COMMAND, determines how best to dose targets.”

COMMAND is a computer algorithm designed to help minimize leakage of therapeutic compounds beyond the bounds of a specific brain area.

It works by using positron emission tomography (PET) scanning to identify the best sites for multiple injections aimed at providing more complete coverage of a brain structure. An advantage of this technique is that it accounts for irregularly shaped brain structures, whose exact contours differ between individuals, while avoiding non-target structures.

“COMMAND applies a simple principle when determining where to place the drug: maximize the amount of drug falling within the target brain structure and minimize tissues exposed beyond the target region,” said Ashvin Bashyam, PhD, one of the study’s co-authors.

PET scans using a specially labeled solution called Cu-64 allowed the team to track the movements of small amounts of fluid (bolus) injected into the striata (the plural of striatum) of rats. They performed this procedure using one, two, and three bolus given in a single infusion (injection) to compare the volume of tissue affected by different numbers of doses.

The single bolus did not cover a substantial portion of the target striata, whereas both of the multi-bolus procedures significantly improved target coverage without loss of accuracy.

“We anticipate that COMMAND can improve researchers’ ability to precisely target brain structures to better understand their function, and become a platform to standardize methods across neuroscience experiments,” said Ann Graybiel, PhD, senior author of the study. “Beyond the lab, we hope COMMAND will lay the foundation to help bring multifocal, chronic drug delivery to patients.”