Medical Device Link.

DESIGN

Neural recording

The in vivo extracellular recording of neurons constitutes the only possibility for investigating the activity of groups of neurons and their link to subject behaviour. Until now, this recording has been achieved in three ways: with the use of needle-like single electrode probes, probes containing groups of electrodes to obtain spatial information, and probe arrays that attempt to gather signals in three-dimensional space. However, these types of arrays are restricted to sampling in a given plane or have difficulty collecting data in complex regions such as those found in highly convoluted cortices.

There is also a need to obtain stable signals over extended recording periods. This is made difficult by the damage inflicted to tissue when the probe array is inserted, physical movement by the subject, and the way tissue responds to the presence of a foreign body. The combination of mechanical effects and the changes in electrode characteristics over time mean this is a significant problem.

The NeuroProbes project

Given the need for a new generation of probe arrays to address these challenges and the desire to incorporate additional functions in a common system, in 2006 the European Commission funded the NeuroProbes Project (www.neuroprobes.org).

This comprises a consortium of 14 institutions divided into three categories: technological, scientific and industrial. Its composition enables NeuroProbes to incrementally develop new technologies, validate them using scientific and clinical tests and exploit the results. Having completed the first of its four years, the project has produced a range of devices that are already undergoing in vivo tests.

Technological innovation

At the heart of the challenge of building probes that interface with tissues in three-dimensional space lies the inherent constraint that microsystems are largely limited to two-dimensional implementation. Therefore, one of the primary missions of the project consisted of conceiving from the start a new integration methodology. This would enable the assembling of three-dimensional microsystems while maintaining compatibility with the requirements of multifunction integration, reconfigurability to suit the various experimental needs, and an overall slim system profile that is conducive to floating operation for chronic applications.

NeuroProbes provides a new modular solution to the integration of multifunctional probes into arrays. Arrays are assembled in a modular fashion similar to the way Lego bricks are put together. In this way, customisation of arrays for diverse application conditions is possible with a combination of diverse functions: electrical recording and stimulation, drug delivery and chemical sensing. Probes of different functionalities, dimensions and configurations can be interchangeably assembled to the array (Figure 1). Furthermore, given the requirement for use in chronic applications, the technology utilises a thin backbone, which allows the array to float with the brain. Additional features include

• integration of electronics and microfluidics to the backbone
• in-plane ultraflexible ribbon cable and fluidic ports
• scalability nearly independent of probe technology
• depth control of probes for fine positioning
• telemetry.

Figure 1: Micrograph of one of the three-dimensional probe arrays currently being tested in NeuroProbes. The device consists of a 4×4 array of 8-mm long probes. Each probe contains five evenly spaced electrodes; it also includes an integrated ultraflexible ribbon cable.

Probe modularity is also important for accessing complex regions of the brain. This technology allows the sharing of probes of multiple dimensions and shapes within the same platform. Thus, it becomes easier to adjust electrode distribution according to a specific complex area such as a sulcus while preserving the ability to obtain accurate anatomical reconstruction, that is, to retrieve the spatial distribution of the electrode array.

Drug delivery

The causal relationship between neural substrate and subject behaviour has been investigated primarily using electrical stimulation, but it can benefit greatly from chemical inactivation. This is done by injecting a substance to silence neural activity in a focal area. Multifunctional arrays such as those developed by the NeuroProbes project are essential in investigations of this type. By combining focal injection with electrical recording, these probes allow monitoring of the extension and duration of the inactivation. The microfluidic capability envisaged in the NeuroProbes technology has the potential to enable simultaneous inactivations in multiple locations. This capability could have an enormous impact on furthering the understanding of the organisation of the prefrontal cortex, which in turn could be valuable in the research of disorders such as attention deficit hyperactivity disorder.

Biosensing

Microdialysis has been the primary focal technique for the study of neuro-chemical processes in the brain, but it is limited in its spatio–temporal resolution and requires subject restraint. Significant improvement has been achieved with the use of probe-based biosensors, but so far they have been mainly limited to standalone configurations. The technology of NeuroProbes allows the combination of biosensors with other kinds of probes such as those for electrical recording, thus allowing spatial correlation of the obtained data. The work of the project focuses on two neuroactive substances: choline and glutamate. Choline sensing is used for the assessment of cholinergic transmission as a substitute for acetylcholine (ACh) detection (ACh sensing requires cholinesterase inhibition, but cholinesterase cannot be used in humans). A potential application is the study of the early cognitive decline in Alzheimer’s disease. Glutamate sensing, which is particularly difficult to do using microdialysis because of the localisation of the areas of interest, is potentially important in the study of schizophrenia.

Biocompatibility

One of the main objectives of this project is to develop technology for use in chronic applications. In parti-cular, it is important to ensure the long-term stability of signal recordings. Although it is important to keep the electrodes free of gliosis, at the same time it is desirable that the array remains stably anchored to tissue. NeuroProbes is investigating forms of actively controlling the interaction of the different probe regions with tissue by acting on the early mechanisms of protein adsorption. The aim is also to avoid interfering with neurite growth or disturbing the neural network.

Outlook

The NeuroProbes project is enabling a new set of tools for neuroscience research and clinical use. By modularly combining multiple features into a common platform, it offers the possibility of tailoring probe configuration to specific experimental or clinical needs. The architecture also permits size scaling, therefore addressing the requirements of denser neuronal populations. Having completed its first year, the project has produced a series of prototypes that are currently undergoing in vivo testing.

In the future, the project aims to address clinical applications, in particular the management of intractable epilepsy (partial refractory seizures as a result of focal cortical dysplasia). It will also extend its activities into electrical stimulation of neurons for application in neural prostheses using the established background of its partners in auditory and visual prosthetic systems.

Herc Neves Ph.D. is Principal Scientist in Biomedical Biosystems at Interuniversity Microelectronics Centre (IMEC), Kapeldreef 75, B-3001 Leuven, Belgium tel. +32 16 28 89 58, e-mail: herc@imec.be, www.imec.be