A Rational Approach to Understanding and Evaluating Responsive Neurostimulation

Closed-loop brain stimulation is increasingly used in level 4 epilepsy centers without an understanding of how the device behaves on a daily basis. This lack of insight is a barrier to improving closed-loop therapy and ultimately understanding why some patients never achieve seizure reduction. We aimed to quantify the accuracy of closed-loop seizure detection and stimulation on the RNS device through extrapolating information derived from manually reviewed ECoG recordings and comprehensive device logging information. RNS System event logging data were obtained, reviewed, and analyzed using a custom-built software package. A weighted-means methodology was developed to adjust for bias and incompleteness in event logs and evaluated using Bland–Altman plots and Wilcoxon signed-rank tests to compare adjusted and non-weighted (standard method) results. Twelve patients implanted for a mean of 21.5 (interquartile range 13.5–31) months were reviewed. The mean seizure frequency reduction post-RNS implantation was 40.1% (interquartile range 0–96.2%). Three primary levels of event logging granularity were identified (ECoG recordings: 3.0% complete (interquartile range 0.3–1.8%); Event Lists: 72.9% complete (interquartile range 44.7–99.8%); Activity Logs: 100% complete; completeness measured with respect to Activity Logs). Bland–Altman interpretation confirmed non-equivalence with unpredictable differences in both magnitude and direction. Wilcoxon signed rank tests demonstrated significant (p < 10−6) differences in accuracy, sensitivity, and specificity at >5% absolute mean difference for extrapolated versus standard results. Device behavior logged by the RNS System should be used in conjunction with careful review of stored ECoG data to extrapolate metrics for detector performance and stimulation. Electronic supplementary material The online version of this article (10.1007/s12021-019-09446-7) contains supplementary material, which is available to authorized users.

The charge density of a selected and/or programmed stimulation is calculated by the programmer. Charge densities greater than 25 μC/cm 2 /phase are not allowed to be selected or programmed into the neurostimulator.

Cathode
The negative pole of an electrode selected for stimulation.

Configure detection
Analysis of detection settings using the programmer detection tools and retrieved neurostimulator ECoG records.

Cortical Strip Lead
The cortical strip lead is intended for subdural implant to provide an interface through which electrical activity of the brain can be monitored and electrical stimulation may be delivered.

Current
The amplitude of current that will be delivered in each phase of a current pulse.

Depth Lead
The depth lead is intended for implant into deep brain structures to provide an interface through which electrical activity of the brain can be monitored and electrical stimulation may be delivered.

Detector channel
The amplifier channel of electrodes selected to detect ECoG activity.

Detection settings
Settings that combine patterns and detection tool settings in order to detect activity.

Detection tools
There are three (3) types of detection tools selectable for Pattern A or Pattern B event detectors. The detection tools are: the bandpass tool, line length tool, and area tool.

ECoG. Electrocorticogram
Electrical activity derived directly from the cerebral cortex. Also used to describe the neurostimulator or programmer stored record of this activity (e.g. "ECoG record").

ECoG activity
ECoG activity refers to activity which is detected by the neurostimulator using one of the event detectors.

ECoG Length
The amount of time stored for a programmer commanded ECoG record.

ECoG storage trigger
The type of neurostimulator activity selected by the user to result in the storage of an ECoG record if the activity occurs.

Episode duration
The time elapsing between the point at which the neurostimulator detects Pattern A or Pattern B to the point at which post-episode baseline activity is detected.

Event
Activity detected by the neurostimulator. Events are considered any of the following: long episodes, pattern A, pattern B, responsive therapy, noise or saturation.

Frequency
The frequency is the rate at which pulses are delivered which is expressed in Hz (pulses/second).

Impedance measurement
The opposition of current flow between electrodes as determined by measuring the voltage (Ohms) resulting from the delivery of a current pulse. A current pulse must be applied to the patient in order to obtain this measurement.

Implant configuration
Information which describes the port(s) to which the proximal end of the lead(s) are connected.

Interrogate
The act of retrieving stored data and settings from the neurostimulator using the programmer.

Line length detection tool
The line length detection tool performs an estimate of the length dimension of a signal related to the complexity of a signal.

Long episode
Initiate ECoG storage when a detected episode continues beyond a preset duration.

Magnet
The magnet suppresses RNS® System therapy as long as the magnet is in position. Placing the magnet over the neurostimulator also triggers a diagnostic, and can also be programmed to trigger ECoG storage.

Montage
Collective term used to describe the assignment of electrode labels and amplifier gain settings to the amplifier channels. Noise 1. An event detector that identifies 60 Hz noise from selected detect channels. 2. Environmental interference in the telemetry between the neurostimulator and wand/programmer.

Overwritten
Once the memory for ECoG or diagnostics is full, the neurostimulator will store new data by overwriting the oldest ECoG records or diagnostics.

Patient Data Management System (PDMS)
The PDMS is a secure web site that provides a means to review information that has been up-loaded by the programmer.

Patterns
Patterns (pattern A and pattern B) use a collection of detection tools to classify electrographic activity.

Post-episode monitoring interval
Responsive therapies will be DISABLED for this period of time after detecting the end of an episode.

Post-episode therapy
Therapy that is delivered following an episode containing responsive therapy. Post-episode therapy will only be delivered if the setting is programmed as ENABLED.

Post-trigger ECoG storage
Neurostimulator setting which indicates the duration of ECoG data that will be stored in the neurostimulator after an ECoG triggering event.

Pre-trigger ECoG storage
Neurostimulator setting which indicates the duration of ECoG data that will be stored in the neurostimulator prior to an ECoG triggering event.

Programmer
The programmer is a laptop personal computer that runs software developed by NeuroPace to communicate with the neurostimulator, to download selected settings into the neurostimulator, and to upload information from the neurostimulator. The programmer communicates with the neurostimulator via the wand. The programmer also communicates with the PDMS via an internet connection.

Programming
Using the programmer to program settings into the neurostimulator.

Pulse
A biphasic waveform of electrical stimulation delivered by the neurostimulator.

Pulse count
The pulse count is the number of times a pulse will be delivered in a burst. This count is calculated and displayed on the programmer for each selected therapy.

Pulse interval type
For responsive therapy bursts, the pulse interval type can be selected as adaptive or fixed.

Pulse to pulse (p-p) interval
The duration between the start of one stimulation pulse and the start of a subsequent pulse.

Pulse-width per phase (PW)
Duration of a single phase within a biphasic pulse, measured in milliseconds.

Recovery period
Period of time after the end of noise detection during which the neurostimulator attempts to determine post-episode baseline activity.

Reset
When the neurostimulator is reset the following will occur: detection and all therapies will be disabled, no ECoGs will be stored, and no diagnostics will be stored (however events prior to reset will be saved). If a neurostimulator reset occurs, the user should note the cause of the reset and contact NeuroPace.

Responsive therapy
Electrical stimulation output to cortical tissue by the neurostimulator in response to pattern A or pattern B detection. RNS® Neurostimulator An implantable, battery powered, microprocessor controlled device that can amplify and analyze the patient's electrocorticographic activity, detect activity from intracranial electrodes and deliver a short train of current pulses to the brain to attempt to interrupt the detected activity.

Saturation event detector
Saturation occurs when an input signal exceeds the dynamic range of a particular channel. The neurostimulator incorporates a saturation detector to reduce occurrences of detecting saturation as a neurological event.

Scheduled ECOG storage
A selectable neurostimulator function that causes the neurostimulator to store an ECoG at the desired time(s) of day.

Stim pathway
Collective term describing the anodes (+) and cathodes (-) selected for a burst.

Storage start time
Scheduled ECoG storage setting controlling the time(s) at which ECoG storage will be triggered.

Summary
Programmer interactive display of a record of the neurostimulator activity occurring since the last interrogation.

Synchronize data
The action of transferring data (via the internet) to the PDMS.

Technical Mode
Option to configure detection using all detection parameters.

Telemetry
Communication between the neurostimulator and the programmer.

Therapy limit per day
Responsive therapy delivery will be DISABLED for the remainder of the day after the programmed number of responsive therapies has been delivered.

Therapy sequence
Responsive therapy is delivered as a therapy sequence of up to 5 individually configured sequential therapies (electrical stimulation) in response to each detected episode.
Supporting Table 1. Glossary of RNS System and related terminology. RNS System definitions reprinted from RNS System Manual with permission.