The development of long-term neural interfaces is one of the important strategic directions for neural probe technologies. A second direction is the development of combined electrical and chemical interfaces to provide a duality of function across the electrical and chemical domains. While electrical charge distributions and potentials are important factors determining neuronal activity, it is well known that complex biochemical reactions within cells are the major mechanism determining their functionality. Thus, in order to obtain a better understanding of neuronal behavior, it is important to be able to deliver chemicals (drugs) to highly localized areas of neural tissue in precise quantities while monitoring the cell responses in vivo. For example, specific molecules, such as calcium, can be delivered to influence cell behavior, and n-methyl-d-aspartate (NMDA) can be delivered to modify synaptic activity (Faingold 1991). In these applications, it is important that the device for injection be very small so as not to disturb the neural system and that it be able to inject fluid volumes in the 10–1000 picoliter (pL) range controllably. In the past, the most commonly used techniques for injecting chemicals into brain tissue have been microiontophoresis (Dionne 1976; Hicks 1984; Timmerman 1997) and pressure ejection (Gerhardt 1987) using single- and multi-barrel glass pipettes. The responses of nearby neurons in these studies were measured using separately positioned pipettes filled with electrolyte. These approaches typically suffer from relatively poor control in positioning the injecting pipette relative to the monitoring points and require hand assembly on a one-at-a-time basis.

In addition to precise and controllable injections of chemicals at the microscale, it is equally important to be able to sample neurochemicals on comparable spatial and temporal scales. Understanding chemical communication between neurons is central to progress in neuroscience. A neuron that receives sufficient input will secrete neurotransmitter at its synapses where the chemical/ion diffuses to the receiving neuron to interact with receptors. Released transmitter is removed from the extracellular space by transporter-mediated uptake or chemical degradation. Over 100 different compounds have been identified as neurotransmitters or neuromodulators including several amino acids, scores of peptides, purines, catecholamines, indoleamines and metal ions. While ex vivo measurements of neurotransmitter release are valuable, understanding neurotransmission ultimately requires in vivo measurements because regulation of neurotransmitters involves interplay of neuronal connections and extracellular milieu that are altered by ex vivo preparations (Obrenovitch 1997; West, A. R. 2002). In addition, correlating behavior with neurotransmitter levels requires in vivo measurements.   

Important criteria for evaluating methodology for in vivo neurotransmitter measurements include sensitivity, selectivity, simultaneous measurement capability, spatial resolution, and temporal resolution. The ability to simultaneously measure neurotransmitters is necessary when studying the interactions of neurotransmitter systems or when the neurotransmitter involved in a behavior or effect is unknown. Spatial resolution is important since many brain structures are small and larger structures have heterogeneity that is lost with poor resolution. Finally, temporal resolution is critical in gaining an accurate reflection of neurotransmitter activity. During behavior or stimuli, neurotransmitters in the extracellular space change concentrations on the second time scale (Stamford 1990; Wightman 1990; Hu 1994; Mitchell 1994; Lada 1998; Kulagina 1999; Sachdev 2000; Burmeister 2002; Huettl 2002; Rossell 2003). At present only a few neurotransmitters have been measured with this temporal resolution and such measurements are usually performed in specialized laboratories. The third objective of the proposed CNCT is to further develop multi-functional probe technologies for combined electrical and chemical interfaces.