Design of a flexible parylene-based multi-electrode array for multi-region recording from the rat hippocampus.

The hippocampus is a critical deep brain structure in several aspects. It is directly related to the formation of new long-term declarative memory. The malfunction of the hippocampus closely relates to various disease and pathological conditions. It is also a model structure for the study of cortical function and synaptic plasticity in general because of its special neuro-anatomical structure and intrinsic connections within the hippocampus formation. Both the understanding of roles that the hippocampus plays in recognition memory and the study of neural plasticity require simultaneously recording of neural activities from multiple sub-regions of the hippocampus from behavioral animals. However the distribution of cells in the hippocampus make the recording from multiple sub-regions a big challenge with the traditional uni-length micro-wire arrays. Well-designed electrode arrays are required to reach multiple regions simultaneously because of the distinctive double C shape of the hippocampus cell body layers. In this work, we designed a multi-shanks electrode which uses Parylene C, a highly biocompatible and flexible polymer, as a base and has multiple recording sites specially positioned along the longitudinal axis to fit the curvy shape of the rat hippocampus.

An in vitro seizure model from human hippocampal slices using multi-electrode arrays.

Temporal lobe epilepsy is a neurological condition marked by seizures, typically accompanied by large amplitude synchronous electrophysiological discharges, affecting a variety of mental and physical functions. The neurobiological mechanisms responsible for the onset and termination of seizures are still unclear. While pharmacological therapies can suppress the symptoms of seizures, typically 30% of patients do not respond well to drug control. Unilateral temporal lobectomy, a procedure in which a substantial part of the hippocampal formation and surrounding tissue is removed, is a common surgical treatment for medically refractory epilepsy. In this study, we have developed an in vitro model of epilepsy using human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. We show that using a planar multi-electrode array system, spatio-temporal inter-ictal like activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) artificial cerebral spinal fluid with 4-aminopyridine (100 µM) added. The induced epileptiform discharges can be recorded in different subregions of the hippocampus, including dentate, CA1 and subiculum. This new paradigm will allow the study of seizure generation in different subregions of hippocampus simultaneously, as well as propagation of seizure activity throughout the intrinsic circuitry of hippocampus. This experimental model also should provide insights into seizure control and prevention, while providing a platform to develop novel, anti-seizure therapeutics.

Recording place cells from multiple sub-regions of the rat hippocampus with a customized micro-electrode array.

The hippocampus is a subcortical structure which is involved in memory function. There is a considerable amount of evidence available which indicates that the hippocampal system is necessary for effective spatial learning in rodents and short-term topographical memory in human. Recordings of neural activities from the hippocampus of behaving animals can help us to understand how spatial information is encoded and processed by the hippocampus. In this work, we designed a triple-region microelectrode array (MEA) which took into concern the anatomical structures of the rat hippocampus. The array was composed of 16 stainless steel wires which were arranged into three groups that differed in length. Each group targeted one subregion of the hippocampus. The array was chronically implanted into the rat hippocampus through craniotomy. Neural activities were monitored both during the implantation and after recovery. The triple-region MEA was capable of recording unitary activities from multiple subregions of the rat hippocampus and the spatial distribution of firing rates were analyzed while the animal freely explored in the environment.

Nonlinear dynamical model based control of in vitro hippocampal output.

This paper describes a modeling-control paradigm to control the hippocampal output (CA1 response) for the development of hippocampal prostheses. In order to bypass a damaged hippocampal region (e.g., CA3), downstream hippocampal signal (e.g., CA1 responses) needs to be reinstated based on the upstream hippocampal signal (e.g., dentate gyrus responses) via appropriate stimulations to the downstream (CA1) region. In this approach, we optimize the stimulation signal to CA1 by using a predictive DG-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and an inversion of the CA1 input-output model (i.e., inverse CA1 plant model). The desired CA1 responses are first predicted by the DG-CA1 trajectory model and then used to derive the optimal stimulation intensity through the inverse CA1 plant model. Laguerre-Volterra kernel models for random-interval, graded-input, contemporaneous-graded-output system are formulated and applied to build the DG-CA1 trajectory model and the CA1 plant model. The inverse CA1 plant model to transform desired output to input stimulation is derived from the CA1 plant model. We validate this paradigm with rat hippocampal slice preparations. Results show that the CA1 responses evoked by the optimal stimulations accurately replicate the CA1 responses recorded in the hippocampal slice with intact trisynaptic pathway.

Spatio-temporal inter-ictal activity recorded from human epileptic hippocampal slices.

Epilepsy is a medical syndrome that produces seizures affecting a variety of mental and physical functions. The actual mechanisms of the onset and termination of the seizure are still unclear. While medical therapies can suppress the symptoms of seizures, 30% of patients do not respond well. Temporal lobectomy is a common surgical treatment for medically refractory epilepsy. Part of the hippocampus is removed from the patient. In this study, we have developed an in vitro epileptic model in human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. Using a planar multielectrode array system, spatio-temporal inter-ictal activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) aCSF with additional 100 µM 4-aminopyridine. The induced inter-ictal activity can be recorded in different regions including dentate, CA1 and Subiculum. We hope the experimental model built in this study will help us understand more about seizure generation, as well as providing insights into prevention and novel therapeutics.

Using an open-loop inverse control strategy to regulate CA1 nonlinear dynamics for an in vitro hippocampal prosthesis model.

A modeling-control paradigm to regulate output of the hippocampus (CA1) for a hippocampal neuroprosthesis was developed and validated using an in vitro slice preparation. Our previous study has shown that the VLSI implementation of a CA3 nonlinear dynamic model can functionally replace the CA3 subregion of the hippocampal slice. The propagation of temporal patterns of activity from DG-->VLSI-->CA1 reproduces the activity observed experimentally in the biological DG-->CA3-->CA1 circuit. In this project, we incorporate an open-loop controller to optimize the output (CA1) response. Specifically, we seek to optimize the stimulation signal to CA1 using a predictive dentate gyrus (DG)-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and a CA1 input-output model (i.e., CA1 plant model), such that the ultimate CA1 response (i.e., desired output) can be first predicted by the DG-CA1 trajectory model and then transformed to the desired stimulation intensity through the CA1 inverse plant model. Laguerre-Volterra kernel model for random - interval, graded - input, contemporaneous - graded -output system is formulated and applied to build the DG-CA1 trajectory model and the CA1 plant model. The inverse model to transform desired output to input is also derived and validated. We validated the paradigm in hippocampal slices, and results showed the CA1 response evoked by the controlled stimulation signal reinstated the CA1 response evoked by the trisynaptic pathway.

A method for unit recording in the lumbar spinal cord during locomotion of the conscious adult rat.

Extracellular recordings from single units in the brain, for example the neocortex, have proven feasible in moving, awake rats, but have not yet been possible in the spinal cord. Single-unit activity during locomotor-like activity in reduced preparations from adult cats and rats have provided valuable insights for the development of hypotheses about the organization of functional networks in the spinal cord. However, since reduced preparations could result in spurious conclusions, it is crucial to test these hypotheses in animals that are awake and behaving. Furthermore, unresolved issues such as how muscle force precision is achieved by motoneurons as well as how spinal neurons are spatio-temporally correlated are better to investigate in the conscious and behaving animal. We have therefore developed procedures to implant arrays of extracellular recording electrodes in the lumbar spinal cord of the adult rat for long-term studies. In addition, we implanted pairs of electromyographic electrodes in the hindlimbs for the purpose of monitoring locomotion. With our technique, we obtained stable long-term recordings of spinal units, even during locomotion. We suggest this as a novel method for investigating motor pattern-generating circuitry in the spinal cord.

Control theory-based regulation of hippocampal CA1 nonlinear dynamics.

We are developing a biomimetic electronic neural prosthesis to replace regions of the hippocampal brain area that have been damaged by disease or insult. Our previous study has shown that the VLSI implementation of a CA3 nonlinear dynamic model can functionally replace the CA3 subregion of the hippocampal slice. As a result, the propagation of temporal patterns of activity from DG-->VLSI-->CA1 reproduces the activity observed experimentally in the biological DG-->CA3-->CA1 circuit. In this project, we incorporate an open-loop controller to optimize the output (CA1) response. Specifically, we seek to optimize the stimulation signal to CA1 using a predictive dentate gyrus (DG)-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and a CA1 input-output model (i.e., CA1 plant model), such that the ultimate CA1 response (i.e., desired output) can be first predicted by the DG-CA1 trajectory model and then transformed to the desired stimulation through the inversed CA1 plant model. Lastly, the desired CA1 output is evoked by the estimated optimal stimulation. This study will be the first stage of formulating an integrated modeling-control strategy for the hippocampal neural prosthetic system.

Custom-designed high-density conformal planar multielectrode arrays for brain slice electrophysiology.

Multielectrode arrays have enabled electrophysiological experiments exploring spatio-temporal dynamics previously unattainable with single electrode recordings. The finite number of electrodes in planar MEAs (pMEAs), however, imposes a trade-off between the spatial resolution and the recording area. This limitation was circumvented in this paper through the custom design of experiment-specific tissue-conformal high-density pMEAs (cMEAs). Four configurations were presented as examples of cMEAs designed for specific stimulation and recording experiments in acute hippocampal slices. These cMEAs conformed in designs to the slice cytoarchitecture whereas their high-density provided high spatial resolution for selective stimulation of afferent pathways and current source density (CSD) analysis. The cMEAs have 50 or 60 microm center-to-center inter-electrode distances and were manufactured on glass substrates by photolithographically defining ITO leads, insulating them with silicon nitride and SU-8 2000 epoxy-based photoresist and coating the etched electrode tips with gold or platinum. The ability of these cMEAs to stimulate and record electrophysiological activity was demonstrated by recording monosynaptic, disynaptic, and trisynaptic field potentials. The conformal designs also facilitated the selection of the optimal electrode locations for stimulation of specific afferent pathways (Schaffer collaterals; medial versus lateral perforant path) and recording the corresponding responses. In addition, the high-density of the arrays enabled CSD analysis of laminar profiles obtained through sequential stimulation along the CA1 pyramidal tree.

VLSI implementation of a nonlinear neuronal model: a "neural prosthesis" to restore hippocampal trisynaptic dynamics.

We are developing a biomimetic electronic neural prosthesis to replace regions of the hippocampal brain area that have been damaged by disease or insult. We have used the hippocampal slice preparation as the first step in developing such a prosthesis. The major intrinsic circuitry of the hippocampus consists of an excitatory cascade involving the dentate gyrus (DG), CA3, and CA1 subregions; this trisynaptic circuit can be maintained in a transverse slice preparation. Our demonstration of a neural prosthesis for the hippocampal slice involves: (i) surgically removing CA3 function from the trisynaptic circuit by transecting CA3 axons, (ii) replacing biological CA3 function with a hardware VLSI (very large scale integration) model of the nonlinear dynamics of CA3, and (iii) through a specially designed multi-site electrode array, transmitting DG output to the hardware device, and routing the hardware device output to the synaptic inputs of the CA1 subregion, thus by-passing the damaged CA3. Field EPSPs were recorded from the CA1 dendritic zone in intact slices and "hybrid" DG-VLSI-CA1 slices. Results show excellent agreement between data from intact slices and transected slices with the hardware-substituted CA3: propagation of temporal patterns of activity from DG-->VLSI-->CA1 reproduces that observed experimentally in the biological DG-->CA3-->CA1 circuit.

Modeling hippocampal nonlinear dynamic transformations with principal dynamic modes.

A new modeling approach of hippocampal nonlinear dynamics is presented. It is based on Principal Dynamics Modes (PDMs) derived from the Volterra kernels quantifying the hippocampal transformations. The approach is illustrated using data obtained from acute hippocampal slice preparations and from behaving rats performs a memory task. The resulting PDM models are comparable in performance to the Volterra models and require significantly less representational and implementational overhead.