**2005 Report submitted by Benchmark Steward(s):**

Brian Litt, M.D. (University of Pennsylvania)

Dennis D. Spencer, M.D. (Yale University)

**Background of the benchmark goal:**

One of the major new areas in epilepsy therapy and investigation is the
design and implementation of systems to predict (or anticipate)
epileptic seizures as they approach and then trigger intervention, such
as focal electrical stimulation, local drug infusion or focal cooling to
arrest seizures before they begin. This work is initially targeted to
helping medically refractory patients who have failed or are not
candidates for resective epilepsy surgery. There is optimism that if
these systems can successfully treat this refractory population, they
could offer an alternative to standard resective surgery or even
multi-drug therapy in some individuals.

**Current status of the field:**

Research into systems for suppressing and modulating seizures continues
to explode in both basic science mechanisms underlying seizure
generation and in clinical translation into human clinical trials.
Leading the areas of focus is research into open loop stimulation of
central brain structures, primarily in thalamic stimulation, to modulate
this process and in responsive stimulation in the epileptic network.
Interest in striato-nigral, central and the subthalamic regions has been
less fruitful than more recent work in the anterior thalamus, mesial
temporal and neocortical regions. Research into animal models of
epilepsy continues to include acute models of seizures (e.g.
pentylenetetrezole), but the focus has switched more to spontaneously
seizing models, particularly systemic pilocarpine and more focal models,
such as intrahippocampal kainate and focal deposition of other
epileptogenic agents. Recordings in both animals and humans are moving
more from single channels at 0.1-100 Hz to arrays of electrodes at much
higher frequencies (i.e. up to 1-2 KHz/ channel). The most important
developments in the field are that preliminary pilot trials of anterior
thalamic and reactive cortical stimulation have progressed to FDA
approval for large-scale clinical trials to prove safety and early
indications of efficacy in anterior thalamic and reactive cortical
stimulation. Development of sensors and algorithms to track seizure
generation continues to progress. There continues to be active
investigation into the analysis of intracranial signals from adults and
children with multifocal epilepsies implanted with intracranial
electrodes, to understand seizure spread in these individuals. Some of
these studies have recently pointed out the importance of high frequency
activity not only in seizure generation in animal models of neocortical
epilepsy, but in humans and basic clinical practice. There is now an
evolution of standard clinical EEG equipment under way to increase the
bandwidth at least into the 500 Hz/ channel range. There is also
interest in new imaging tools to study non-invasive, real-time imaging
correlates of seizure generation and spread. It is hoped that these
types of studies may help identify central regions that are and can be
activated to suppress poorly localized, multifocal or refractory
seizures.

The ability to sample the brain extracellular fluid space in vivo
provides a critical dimension to the study of epileptogenic mechanisms.
Measurements of neurotransmitters and other neuroactive molecules
provide a picture of cerebral metabolism during the interictal baseline
and with continuous monitoring may identify reproducible biochemical
changes preceding and during an ictal event. Microdialysis has been a
common technique employed in animal models and slices. It enjoys
picomolar detection but usually samples a large volume of 200-300 μm by
1-4 mm with a slow time resolution of minutes and must be analyzed off
line under most circumstances. The alternative and actually
complimentary technique for ECF sampling is the voltammetric biosensor
that uses microelectrodes (5-30 μm OD) with smaller spatial (5-30 by
30-150μm) and rapid temporal resolution (1-200 Hz). Voltammetric
detection limits are also not as sensitive as microdialysis (25-50 μm)

Microdialysis has been used in human recordings coupled to depth
electrodes. The data has been very valuable but the technique is very
labor intensive and requires a sophisticated team. The biosensory
technology has the potential to provide robust reliable sensing that
might be more universally applied to human epilepsy.

**Activities update:** (Continued from Benchmark IIIC)

A multicenter clinical trial of closed-loop brain stimulation for
refractory partial (focal and multifocal) epilepsy got underway
(sponsored by NeuroPace, Inc.). Rapid progress toward the goal of 200
patients enrolled is being made, with over 30 patients implanted at the
present time. Preliminary results are not yet available for publication.
A second preliminary study supporting this work was published (12).

A multicenter clinical trial of open-loop brain stimulation of the
anterior thalamic nucleus for refractory partial (including multifocal)
epilepsy got underway (sponsored by Medtronic, Inc.). Rapid progress is
being made toward the planned enrollment of \~200 patients nationwide.
No preliminary results are available. A study of reactive closed-loop
brain stimulation brain stimulation, using an external version of the
NeuroPace implantable device was published in Epilepsia (13). This study
focused on 4 patients treated at one center, all of who had significant
clinical response and no side effects to reactive brain stimulation.

Several studies of high frequency activity ranging from 80 to \>500 Hz
were published in animal models and humans. Several were very
encouraging regarding the potential of these recordings to map the
epileptic network and track seizure generation, particularly in the
neocortex (14-17).

Significant progress has been made in beginning to understand the
mechanisms through which electrical stimulation can be used to modulate
neuronal function. This progress includes studies that match
computational and modeling studies together with experimental
measurements in humans and animal models of neurological disorders
(18-20). Other studies, consisting primarily of computational modeling
are of interest, but await validation through clinical and animal
studies to determine their relevance (21-24).

There remains active investigation into other methods of novel focal
therapy for refractory multi-focal and neocortical epilepsy including
focal thermocoagulation (25), focal cooling with implantable peltier
devices (26), as well as continued research into local drug delivery in
brain.

There continues to be incremental progress in algorithms for detecting
and predicting seizures that is applicable to implementation in systems
for treating refractory epilepsy. Seizure prediction/ anticipation
continues to be a field fraught with controversy, though there is
growing consensus on targets, requirements for statistical validation,
and for what constitutes significant results. These ideas will be better
articulated in the summary of papers and methods presented at the First
International Collaborative Workshop on Seizure Prediction, currently in
press in the journal Clinical Neurophysiology.

Since our last benchmark report, a collaboration has been established
between the Yale Epilepsy Program and Greg Gerhardt, who directs the
Center for Sensory Technology at the University of Kentucky. His
ceramic-based voltammetric electrodes have been successfully coated with
glutamate oxidase and neurotransmitter data obtained in brain slices and
in vivo animals. At present, these electrodes are being adapted to the
Yale microdialysis/depth electrodes and an IRB protocol is being written
for human use during intracranial AVEEG recordings.

In order to stimulate and provide guidance for this technology in
epilepsy, we are planning a workshop. An application for a NIH sponsored
meeting will be submitted this spring for the late winter/early spring
of 2006. The purpose of this workshop will be to:

> 1\) Evaluate the technological state of CNS sensing. How do the
> available techniques compare and perform particularly regarding the
> special requirements of monitoring the dynamic state of the
> epileptogenic region compared to the more static requirements, in
> Parkinson's disease, for example?
>
> 2\) What data exists thus far in using these techniques for epilepsy
> investigation?
>
> 3\) What data exists in using biosensors for other CNS investigations
> both for study of the normal ECF milieu and in disease states (trauma,
> neurodegenerative diseases, etc.)?
>
> 4\) What new techniques are being developed for future sensing
> devices? How can we guide that process especially for epilepsy's
> special needs?
>
> 5\) How would we like to use this technology in the future?

An outline of a one- or two-day workshop would therefore have the
following structure:

I. Introduction to measuring cerebral metabolism and neurochemical
dynamics, why is it worthwhile?

II\. Comparing sensing techniques

A. Overview

B. Microdialysis

C. Voltammetric

D. Fiber Optic

Panel discussion

III\. Biosensing in normal and diseased states other than epilepsy

A. Microdialysis

B. Voltammetric

C. Fiber Optic

Panel discussion

IV\. Biosensing in epilepsy

A. Microdialysis

B. Voltammetric

C. Fiber Optic

Panel discussion

V. Future sensing devices

VI\. Future demands for biosensing in epilepsy

**Top priorities for next 5-10 years:** (Continued from Benchmark IIIC)

-   To identify central pathways, circuits and mechanisms which, when
    activated, can suppress or modulate focal or multifocal seizures,
    particularly those of neocortical origin.

-   To identify methods for determining where, when and how to deliver
    local therapy, such as electrical stimulation, focal cooling or
    local drug infusion to these areas. Very important to this goal are
    methods to identify periods of increased probability of seizure
    onset ("Seizure Prediction").

-   To validate the above two discoveries in spontaneously seizing
    animal models of epilepsy and translate them into human therapy
    though novel surgical, minimally invasive or non-invasive methods.

**Roadblocks to progress:** (Continued from Benchmark IIIC)

-   The relative inaccessibility of large areas of brain to
    intracranial, high frequency electrophysiological recording in
    humans, due to patient safety concerns and the lack of noninvasive
    methods, such as scalp EEG, to capture these signals.

-   Lack of understanding of mechanisms of seizure generation in human
    partial epilepsy.

-   Lack of understanding of the mechanisms by which brain stimulation
    works to modulate/ inhibit neuronal function.

-   Lack of methods to localize and record from the epileptic network
    essential to generate seizures.

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