Advances in the application of technology to epilepsy: the CIMIT/NIO Epilepsy Innovation Summit

Abstract

In 2008, a group of clinicians, scientists, engineers, and industry representatives met to discuss advances in the application of engineering technologies to the diagnosis and treatment of patients with epilepsy. The presentations also provided a guide for further technological development, specifically in the evaluation of patients for epilepsy surgery, seizure onset detection and seizure prediction, intracranial treatment systems, and extracranial treatment systems. This article summarizes the discussions and demonstrates that cross-disciplinary interactions can catalyze collaborations between physicians and engineers to address and solve many of the pressing unmet needs in epilepsy.

Fig. 1.

MR images of rats #1, 2, and 3 (top to bottom) are shown before (left column) and after (middle column) tail vein injection of AMT-MNPs (3.7 mg Fe/kg). Rat #1 showed bilateral uptake of particles, rat #2 showed unilateral uptake, and rat #3 did not show any particle uptake. Arrows in the left column show the areas of hippocampal atrophy due to kainic acid injection. Rats #1 and 2 had spontaneous behavioral seizures; rat #3 did not show any behavioral seizure activity. The location of areas with AMT-MNP uptake is shown in the right column on sections from Paxinos [1]. Images were taken 6 h after AMT-MNP injection for rats #1 & 3, and 4h after injection for rat 2.

Fig. 2.

Left: Rate of interictal spikes in rat 1 with bilateral AMT-MNP uptake recorded during 30 min of immobility and slow wave sleep in the left (a) and right (b) dentate gyrus; (c) peri-event histogram of interictal spikes recorded in the left dentate gyrus versus right dentate gyrus. The rate of interictal spikes was the same on both sides. Right: rate histogram of interictal spikes recorded in the left (d) and right (e) dentate gyrus during 30 min of immobility and slow wave sleep in rat 2, which showed uptake of AMT-MNPs in the right hippocampus; (f) peri-event time histogram for interictal spikes recorded in the left dentate gyrus versus right dentate gyrus. Most interictal spikes occurred on the right, the side of AMT-MNP uptake.

Fig. 3.

Cutaway view of fEEG electrode and reference layer. The scalp electrode (pink) and reference electrode (green) are closely matched spatially to match loop areas, with a carbon wire pair (not shown) terminating at the connector posts on the left. The reference electrode is in direct contact with the reference layer (labeled “hydrogel”) and is electrically insulated and sealed from the scalp electrode. Scalp prep is applied through the center hole in the assembly, with a small column of standard electrode gel used to make electrical connection from scalp to electrode. The “sealer cap” and “primary cap” are flexible and waterproof to allow a snug fit to the contours of the scalp and insulate the reference from the body.

Fig. 4.

Picture of original high-resolution SPECT apparatus.

Fig. 5.

Inside of original machine.

Fig. 6.

Diagram of detectors and collimators.

Fig. 7.

Raster motion of “focal spot.”

Fig. 8.

Dopamine radioligand showing NeuroFocus on left versus standard SPECT system on the right. The small images are of small 1-cc radiomarkers placed on scalp for registration. Note the resolution difference in how standard SPECT tends to “blur” the signal.

Fig. 9.

Image of focal region of hyperperfusion in neurosurgical patient.

Fig. 10.

Small, portable, high-resolution SPECT device (NeuroLogica Corp., Danvers, MA, USA) that can be brought into an epilepsy monitoring unit to scan a patient in the hospital bed.

Fig. 11.

Illustration of fused images for surgery planning. T1 and functional MRI activation region (a); T1 and colored fractional anisotropy (b); DTI, tractography and T1 image (c).

Fig. 12.

Illustration of intracranial EEG-based surgical planning. Blue, electrodes; orange, right-hand activations; gray, left-hand activations; red, lesion.

Fig. 13.

(a) Lateral radiograph and sketch of locations of recorded subdural electrodes. (b) Results of electrical stimulation mapping that were gathered over 5 h. Blue and yellow circles indicate sites that produced receptive aphasia and anomia, respectively. (c) Results of ECoG-based real-time mapping that were gathered in only 2 min. The subject performed a receptive language and naming task in response to visual cues. The SIGFRIED package visualized the change in ECoG signals in mu/beta frequencies (compared with a previously recorded baseline) in real time. Two columns of figures show the display to the investigator at 60 and 120 s. The results of the passive real-time mapping of language are concordant with the results of electrical stimulation (see blue and yellow arrows corresponding to receptive language and naming, respectively).

Fig. 14.

Microelectrode arrays. Top, laminar microelectrode array [8]. Middle, NeuroPort system [6,7]. Bottom, Adtech microwire array.

Fig. 15.

(A) Modulated imaging (MI) system. CCD, charge-cooled device. DMD, digital micromirror device. BPF, bandpass filter. M, mirror. (B) The MI system is combined with EEG cortical microelectrode recording. Insets: Representative D/C and A/C modulated images generated by imaging with spatially modulated incident light. (C) Electroencephalographic recordings and optical scattering measurements following systemic administration of the convulsant pentylenetetrazol (PTZ). The optical scattering coefficient is derived using the MI system. Note synchronized seizure onset (SZ) in two separate cortical electrodes (red and blue) at a defined latency following PTZ injection. Prior to electroencephalographic seizure onset, there is a clear reduction in optical scattering at 850 nm (green), optically identifying the “preseizure state.” Inset: Optical lead time defined as time at optical “trigger” (2SD change in optical scattering from baseline) to time of EEG seizure onset. Mean optical lead time was 118 s (range: 33–284).

Fig. 16.

(A) Broadband optical spectroscopy in vivo. (B) Dual fiberoptic (source/detector) stereotactically co-implanted into mouse hippocampus with bipolar EEG recording electrode. Concurrent EEG and optical recordings are then obtained from the in vivo hippocampus. (C) Example of fiberoptic seizure detection. Optical trigger occurs ~53 s prior to EEG seizure onset.

Fig. 17.

An example of detecting evoked visual hemodynamic responses in a human subject as a demonstration of the novel global interference cancellation technology. (A) Probe configuration for the vision test. (B) Vision stimulation: alternating counter-phased radial checkerboard. (C) Rest period: uniform field with a central fixation cross. The first row of the time series is the target O₂Hb measurements from S-D2 with 4.5 cm source-detector separation. Although the target dataset was expected to contain an increase in O₂Hb following stimulus onset (and concomitant decrease following stimulus offset), the raw time series does not show any obvious expected signal change. The second row is the reference measurements from S-D1 with 1.5 cm source-detector separation. The fact that the signal variations in the target O₂Hb closely match those of the reference O₂Hb (which should contain no visual response) suggested that indeed global interference may dominate the target dataset. The last row is the adaptive filtering result for the target measurement (also with sensitivity correction to cancel the partial volume effect). We see that after adaptive filtering the interference is substantially reduced, and the expected increase following stimulation onset and return to baseline during rest periods are clearly shown. The temporal changes are appropriately associated with the stimulation paradigm.

Fig. 18.

A closed-loop living electrode prosthetic for epilepsy.

Fig. 19.

Photograph of the fabricated 54,000 transistor microchip. The chip is roughly 4 × 4 mm.

Fig. 20.

(a) Statistics of the focal seizure-preventing effect of transmeningeal muscimol in rats. EEG seizure duration ratio = EEG seizure duration in minutes/acetylcholine exposure duration (9.5 minutes). ACSF, artificial cerebrospinal fluid. (b) The dual peristaltic minipump unit of the subdural HNP, with its cover removed to illustrate the inner structure.

Fig. 21.

Comparison of the extracellular fluid concentration for intraparenchymal bolus deposition (focal injection) and intraparenchymal convection enhanced delivery. The region perfused is delimited by the dashed lines. With bolus deposition, solute is distributed by diffusion, resulting in a rapidly declining concentration gradient throughout the region perfused. In contrast, convection enhanced delivery provides a uniform concentration throughout the region perfused with a sharp drop-off in concentration at the borders. (From [16], with permission).

Fig. 22.

Photograph of the RNS™ System neurostimulator and schematic of the neurostimulator sited in the cranium and connected to one depth lead and one subdural strip lead.

Fig. 23.

Drawing showing bilateral leads, extensions and neurostimulator (Kinetra; Medtronic).

Fig. 24.

SANTE study design.

Fig. 25.

Top left-hand panels depict six seizures recorded from one (representative) rat using subdural electrodes (activity from only one contact is shown) each treated with a total of six monophasic (cathodal) pulses delivered through the electrodes adjacent to those used for recording. Top right-hand panels depict two seizures treated with single monophasic (cathodal) pulses (5 mA, 100 μs) also delivered adjacent to the recording electrodes (same rat). The numbers on top of each tracing to the left of the stimulation artifacts in each panel correspond to the “rhythmicity index,” a measure of similarity between successive signal waveforms, computed using software developed by these investigators. Magnified view of six tissue impulse responses to each of the six monophasic pulses delivered over 0.12 s to seizure 6. The probability of seizure blockage is clearly a function of rhythmicity index value. The impulse responses to cathodal stimulations show subtle phase changes (resetting), possibly illustrative of their trajectory to the “null space” or “black hole” from where they cannot “escape” unless suitable stimuli are applied. Cardiac standstill and death (unless timely medical intervention occurs) caused by closed chest trauma exemplify the phenomenon of annihilation of biological oscillations and the existence of “black holes” in certain biological systems such as the heart. As an electrically oscillatory system, the brain likely also has “black hole(s).”

Fig. 26.

(A) Photograph of two Peltier devices. On the bottom is a conventional device similar to those used in experimental epilepsy work to date. The smaller device on top was fabricated using new layering technology that is capable of generating ultrathin Peltier devices that are more efficient energetically. These latter devices would be more suitable for biomedical applications. (B) Photograph of a UV LED. The arrow points to the actual light-generating element. The scale in the lower right corner is 1 mm and applies to both (A) and (B).

Fig. 27.

EEG tracing of a spontaneous seizure (begins following the 322-s mark) with 3- to 4-Hz rhythmic activity seen on channels T4–T6, F4–C4, and C4–P4. The algorithm detected the seizure at the 324.5-s mark after which the electromagnet was energized, thereby initiating on-demand VNS following the 328-s mark (appears as a spike train on the VNS channel). The 6-s delay between seizure onset and the appearance of the VNS spike train is the sum of the following latencies: 2.5-s detection delay, 1.5- electromagnet on-time delay, and 2-s VNS startup time delay.