IEEE Circuits and Systems Magazine - Q3 2022 - 23

Abstract
Closed-loop vagus nerve stimulators (VNSs) are used to treat
refractory epilepsy (RE) and provide an alternative treatment
modality with fewer side effects for RE. This work proposes a
closed-loop VNS that senses the scalp EEG via a wearable EEG
recorder (WER) and stimulates the vagus nerve via an implantable
VNS (IVNS), the combination of which is referred to as a
" HybridVNS " . First, the architecture and system control (by an
App) of the HybridVNS are presented. Next, discrete component
implementations of its key building blocks including the multichannel
preamplifier, pulse generator and wireless power link
are provided. Further, a 4-channel preamplifier magnifies the
recorded EEG signals, and each channel consists of a capacitively
coupled instrumentation amplifier (CCIA) cascaded by a
2nd-order low pass filter. The measured gain and the input-referred
noise (IRN) of the preamplifier are 45.8 dB and 4.9 μVrms
(1 Hz-200 Hz), respectively. We propose a switched-resistor array
pulse generator for constant-current stimulation, and a novel
distance-frequency adaptive inductive coupling link (DFAICL) to
automatically tune the resonance frequency. A maximum wireless
power transmission efficiency of 17% is achieved in the
DFAICL when the supply power is 30dBm and the distance is
20 mm at 2 MHz. Finally, we demonstrate that in the WER, the
onset of an epileptic seizure can be detected by a threshold of
coastline length (294 μV) combined with a threshold of slope
(7.3 μV/ms) within a unit time segment (780 ms), which provides
an average accuracy of 88.2%. The feasibility of the IVNS was
tested in an acute rodent epilepsy experiment. However, the
closed-loop experiment was not conducted.
I. Introduction
E
pilepsy is one of the most common chronic brain
diseases, and it affects people of all ages. Second
to headache, more than 50 million people worldwide
suffer from epilepsy [1]. Approximately 70% of epilepsy
victims could be seizure-free if properly treated
with drugs, while the other 30% are drug resistant, which
is a condition known as refractory epilepsy (RE). RE can
be treated by surgically removing the lesion area directly;
however, this may cause uncertain sequelae and complications
such as memory impairment, field-of-vision loss,
or movement malfunctions.
RE can also be treated with an implanted vagus nerve
stimulator (VNS), which can reduce the frequency and intensity
of epileptic seizures and improve the quality of life of
the patient with fewer side effects [2]. VNS-related clinical
experiments and large-scale case studies have shown that
after VNS therapy, seizures completely stopped in up to 9%
of RE patients, decreased by more than 50% in 55% of the
patients, and were ineffective in approximately 10% of the
patients [3]. Early clinical trials have also shown that VNS
therapy has a cumulative effect. It has been reported that
the seizure frequency decreased by 14%, 25%, 29%, 29%,
43%, and 50% in 85 adult patients (whose average course of
epilepsy was 23 years before treatment) who were treated
with the VNS over 1-6 years, respectively [4]. A 5-year follow-up
study of 90 patients (who received VNS treatment
via a multicenter and public labeling method) was conducted,
and reduction rates of 44.4% in 1 year, 58.7% in 2 years,
and 64.4% in 5 years were found. The seizure frequency
decreased by more than 90% in 14 patients, and 5 patients
were seizure-free [5]. In a clinical study in children, it was
found that VNS therapy had a strong relationship with epilepsy
type, and it was concluded that VNS had the best effect
on myoclonic seizures, a good effect on axo-rhizomelic
tonic seizures, and the least effect on tonic-clonic seizures
[6]. These series of experimental results proved that the
longer the VNS treatment for epilepsy, the better the outcome.
Moreover, researchers found that VNS can improve
the memory function of patients (such as those suffering
from Alzheimer's) while being used to treat RE [7].
Compared to the commonly-used open-loop VNS, the
emerging closed-loop VNS can sense and detect epileptic
activities in real time (by means of a feedback network fulfilled
by the recording path), deliver the electrical pulses
with optimal parameters based on the response of the
stimulation (which is known as responsive stimulation or
stimulation on demand), and immediately suppress seizures
to achieve greater treatment efficacy [8], less power
dissipation, and longer battery life [9]. Many electrophysiological
signals such as the electrocardiogram (ECG), the
electrocorticogram (ECoG), compound action potentials
(CAP), and the electroencephalogram (EEG) can be utilized
to enable closed-loop VNS, resulting in different system
architectures. The criteria for judging the feasibility of
these architectures are whether the system can 1) reliably
detect or predict epileptic seizures, 2) effectively reduce
seizure frequency and/or duration, and 3) easily be accepted
by both patients and their families. With these criteria
in mind, we propose a closed-loop VNS that combines a
wearable EEG recorder (WER, for sensing the scalp EEG)
with an implantable VNS (IVNS) to build a feasible solution
of RE treatment. The system is named HybridVNS.
Although either " epilepsy detection based on EEG
recording " or " VNS " have been investigated extensively,
to the authors' best knowledge, this is the first system design
of a HybridVNS that combines both of them to form
a closed-loop neuro-stimulator (CLNS). In addition, a
thresholding epileptic seizure detector that contains two
featured thresholds is proposed to detect seizure onset.
Xiaolong Li, Jin Zhu, Wei Zheng, Guojun Ma, Xiaoqiao Deng and Weijia Huang were with the School of Electronics and Information, Jiangsu University
of Science and Technology, Zhenjiang, China (e-mail: lixiaolong@just.edu.cn). Ming Yu was with the Department of Neurology, Affiliated Hospital of
Jiangsu University, Zhenjiang, China (e-mail: yuming7251@163.com). Wouter A. Serdijn was with the Section Bioelectronics, Delft University of Technology,
Delft, The Netherlands (e-mail: w.a.serdijn@tudelft.nl).
THIRD QUARTER 2022
IEEE CIRCUITS AND SYSTEMS MAGAZINE
23

IEEE Circuits and Systems Magazine - Q3 2022

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