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Titre: A novel neural prosthesis providing long-term electrocorticography recording and cortical stimulation for epilepsy and brain-computer interface

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LABORATORY INVESTIGATION

A novel neural prosthesis providing long-term
electrocorticography recording and cortical stimulation
for epilepsy and brain-computer interface
Pantaleo Romanelli, MD,1 Marco Piangerelli, PhD,2 David Ratel, PhD,3 Christophe Gaude, MSc,3
Thomas Costecalde, PhD,3 Cosimo Puttilli, MSc,1 Mauro Picciafuoco,1 Alim Benabid, MD, PhD,3
and Napoleon Torres, MD, PhD3
AB MEDICA S.p.a., Cerro Maggiore(MI), Milan; 2Computer Science Division, School of Science and Technology, University
of Camerino, Italy; and 3Biomedical Research Center, Polygone Scientifique Grenoble (CLINATEC Campus), University of
Grenoble Alpes, Grenoble, France
1

OBJECTIVE  Wireless technology is a novel tool for the transmission of cortical signals. Wireless electrocorticography
(ECoG) aims to improve the safety and diagnostic gain of procedures requiring invasive localization of seizure foci and
also to provide long-term recording of brain activity for brain-computer interfaces (BCIs). However, no wireless devices
aimed at these clinical applications are currently available. The authors present the application of a fully implantable
and externally rechargeable neural prosthesis providing wireless ECoG recording and direct cortical stimulation (DCS).
Prolonged wireless ECoG monitoring was tested in nonhuman primates by using a custom-made device (the ECoG implantable wireless 16-electrode [ECOGIW-16E] device) containing a 16-contact subdural grid. This is a preliminary step
toward large-scale, long-term wireless ECoG recording in humans.
METHODS  The authors implanted the ECOGIW-16E device over the left sensorimotor cortex of a nonhuman primate
(Macaca fascicularis), recording ECoG signals over a time span of 6 months. Daily electrode impedances were measured, aiming to maintain the impedance values below a threshold of 100 KW. Brain mapping was obtained through
wireless cortical stimulation at fixed intervals (1, 3, and 6 months). After 6 months, the device was removed. The authors
analyzed cortical tissues by using conventional histological and immunohistological investigation to assess whether
there was evidence of damage after the long-term implantation of the grid.
RESULTS  The implant was well tolerated; no neurological or behavioral consequences were reported in the monkey,
which resumed his normal activities within a few hours of the procedure. The signal quality of wireless ECoG remained
excellent over the 6-month observation period. Impedance values remained well below the threshold value; the average
impedance per contact remains approximately 40 KW. Wireless cortical stimulation induced movements of the upper and
lower limbs, and elicited fine movements of the digits as well. After the monkey was euthanized, the grid was found to be
encapsulated by a newly formed dural sheet. The grid removal was performed easily, and no direct adhesions of the grid
to the cortex were found. Conventional histological studies showed no cortical damage in the brain region covered by
the grid, except for a single microscopic spot of cortical necrosis (not visible to the naked eye) in a region that had undergone repeated procedures of electrical stimulation. Immunohistological studies of the cortex underlying the grid showed
a mild inflammatory process.
CONCLUSIONS  This preliminary experience in a nonhuman primate shows that a wireless neuroprosthesis, with related long-term ECoG recording (up to 6 months) and multiple DCSs, was tolerated without sequelae. The authors predict

ABBREVIATIONS  BCI = brain-computer interface; DCS = direct cortical stimulation; ECoG = electrocorticography; ECOGIW-16E = ECoG implantable wireless 16-electrode; EEG = electroencephalography; GFAP = glial fibrillary acidic protein; Iba-1 = ionized calcium-binding adapter molecule–1; ISO = International Organization for Standardization; MICS = Medical Implant Communication Service; NT = neoformed tissue; SSEP = somatosensory evoked potential; Vim = vimentin.
SUBMITTED  February 17, 2017.  ACCEPTED  October 16, 2017.
INCLUDE WHEN CITING  Published online May 11, 2018; DOI: 10.3171/2017.10.JNS17400.
©AANS 2018, except where prohibited by US copyright law

J Neurosurg  May 11, 2018

1

P. Romanelli et al.

that epilepsy surgery could realize great benefit from this novel prosthesis, providing an extended time span for ECoG
recording.
https://thejns.org/doi/abs/10.3171/2017.10.JNS17400

KEYWORDS  ECoG; electrocorticography; cortical stimulation; epilepsy; brain-computer interface; wireless
neuroprosthesis

I

patients with refractory epilepsy or brain tumors,
electrocorticography (ECoG) and direct cortical
stimulation (DCS) are the gold standard intraoperative techniques used to identify the tissue for resection,
particularly with regard to neighboring eloquent cortex.6,7,9,16,19,30,38 DCS consists of application of an electrical
stimulus directly to the cortex, to assess the contralateral
muscle contraction or the related electromyography discharge, in anesthetized patients. Moreover, it can be used
to generate transient language and behavioral effects in
awake patients while they perform motor or cognitive
tasks.19,30 DCS allows precise mapping of cortical organization in patients undergoing a resective procedure,
providing a valuable instrument to spare the resection of
eloquent cortex and to avoid catastrophic neurological
sequelae.16,17,30 Intraoperative DCS is especially useful in
neurosurgical procedures involving the resection of gliomas close to or involving eloquent cortex, because it allows the surgeon to maximize the extent of the resection
and to prevent neurological injury.17
Electrocorticography offers the additional opportunity
to record the remote effect of electrocortical stimulation
without distortion within a limited distance of a few millimeters, and can provide further details about the functional reorganization caused by the individual’s brain pathology.16,19,26 Moreover, given the high spatial (approximately 1
mm) and temporal (within the timescale of neural activity)
resolution, ECoG recording is essential to identify an ictal focus generating drug-refractory seizures and to guide
the resection. ECoG signal analysis is a valuable emerging tool for both brain mapping10,14,15 and BCI,5,18 due to
its high signal-to-noise ratio. It allows the examination
of high-frequency bands (unavailable for scalp electroencephalography [EEG] recordings) and allows the use of
spectral analysis ECoG recording from sensorimotor cortex.14 At the current state of art, this method provides the
most effective tool for brain-computer interface (BCI) applications, i.e., to drive robotic prostheses and to enhance
neurorehabilitation.21,27,28,35,42
The available commercial ECoG systems require cables connecting the subdural grid with an external recording system. The cables connecting the electrodes placed
on the cortex with the external apparatus leave the skull
through a subcutaneous channel, thus providing a path for
CSF leakage and consequent meningeal infection.4 The
patient undergoing invasive monitoring for epilepsy needs
to be confined to a special recording room under careful
but necessarily short observation. In cases in which no seizures are recorded, the wound is reopened and the grid
removed. In essence, the use of cables connecting the epicortical grid with an external device is the most significant
shortcoming of current ECoG techniques because it allows only short-term recordings, with the risk of meninge2

n

J Neurosurg  May 11, 2018

al and cerebral infection growing steadily day by day.20,31
Here we describe our second experience with a long-term
implantable wireless ECoG device allowing prolonged (up
to 6 months) wireless recording. A first pilot procedure
in which a preliminary device was used is described in
Piangerelli et al.,32 and medium-term electrophysiological
testing performed 3 months after implantation is also described in Zippo et al.47

Methods

Surgical Procedure
In this study, we used a male macaque monkey (Macaca fascicularis) weighing 6.95 kg. The experimental
protocol was approved by the regional committee (Cometh [Committee on Ethics] Grenoble) and registered to
the national committee under the number 12/136 ClinatecNTM-01. The experiment complied with the EU (European Union) directive approved on September 22, 2010
(2010/63/EU), on the care and use of laboratory animals.
A 4.7-T MRI study was performed before the craniotomy
(BioSpec; Bruker BioSpin) to provide image guidance for
the placement of the grid above the sensorimotor cortex.
The animal was anesthetized using a loading dose of 5 mg/
kg xylazine and 20 mg/kg ketamine hydrochloride administered intramuscularly, and then a maintenance dose of
1.25 mg/kg and 5 mg/kg xylazine and ketamine, respectively. Physiological parameters were monitored by the
veterinarian staff during the surgical procedure: heart rate,
blood pressure, respiratory depth, and body temperature.
Standard aseptic conditions were guaranteed during the
surgical procedure. When deep anesthesia was achieved,
the animal was secured to a stereotactic frame and a 3 ×
2.5–cm square craniotomy was performed over the left
sensorimotor cortex, aiming to center the grid placement
over Brodmann area 4. The dura mater was cut in a Y fashion, and the flaps were retracted and sutured on the sides to
expose the central sulcus and the surfaces of the primary
motor (M1) and sensory (S1) cortex. Radiographic images
were acquired during surgery to guide device placement.
Electrophysiological confirmation of motor cortex localization was obtained through cortical stimulation with
bipolar wand intraoperative neural monitoring (ISIS; INOMED Medizintechnik GmbH).
The grid was centered above the hand knob of the left
motor cortex (Fig. 1), and then the dura was extended over
the grid without suturing it, to avoid excessive pressure
over the stem in the subdural penetration point. A silicone
adhesive (KWIK-SIL—a translucent silicone elastomer
with medium viscosity) was applied over the dura to facilitate the closure and to avoid contact between bone cement and cortex. We used KWIK-SIL elastomer because
it produces only a small amount of hydrogen gas during

P. Romanelli et al.

FIG. 1. Intraoperative photograph showing device placement over the
motor cortex: the central sulcus is visible under the grid. L = left; R =
right. Figure is available in color online only.

condensation (the traditional room temperature–vulcanizing silicone systems produce toxic chemicals).3
The bone removed during the craniotomy was replaced
and affixed with screws and plates. We avoided damage
to the grid stem by excessive pressure or overbending.
Finally, bone cement was applied around the grid case to
smooth the edges and provide better protection to the case.
Once the cement became solid, the wound was washed
and closed with sutures. Antibiotics (Augmentin, 14 mg/
kg) were given intramuscularly, and the animal was placed
in the observation cage with heating pads.
The 16-Electrode Device
The device called the ECoG implantable wireless
16-electrode (ECOGIW-16E) monitor (patent numbers
US9031657 B2, EP2699145 B1, AU2012245942 B2,
JP2014514944 A, and CN103648367 A) was designed specifically for monkeys.32 It consists of 2 parts (Fig. 2): the
grid and the body. The grid is a single sheet of flexible
polyimide support that integrates 16 platinum electrodes.
The body, cased in polyetheretherketone, includes a microcontroller handling local processing and a transceiver
module for implantable medical applications within the
Medical Implant Communication Service (MICS) band
(402–405 MHz), with an 800/400/200 kbps raw data
rate. In addition, it includes a triaxial accelerometer, a
stimulus generator, a sensor of temperature and load current, and a lithium-ion battery (3.6 V, 150 mA/hr; International Organization for Standardization [ISO] 13485).
A polyetheretherketone case was chosen for its high and
well-documented biocompatibility in prostheses in different fields of medicine.34 Finally, we have adopted a charging apparatus to provide an induction charger (250 mW,
70 mA at 3.7 V) for a wireless rechargeable battery. The
interface consumes 58 mA (16 channels at 500 samples
per second [SPS] + radio link), 30 mA (16 channels at 500
SPS), and 7 mA in standby mode.
The device was positioned orthogonally and the grid
was centered above the hand knob of the left motor cortex

FIG. 2. The scheme of the ECOGIW-16E. Measurements are in millimeters (mm). Figure is available in color online only.

(Fig. 1), also providing coverage of the central sulcus and
part of S1.
Wireless Recharging Cage
The ECOGIW-16E device is wirelessly rechargeable
using a special cage for nonhuman primates that was developed by Aethra Telecommunication Co. to recharge
the device. The cage (patent numbers EP2755469 B1,
US2015180267, AU2013278927 B2, and CN104427864
A) is a nylon structure containing coils for electromagnetically induced high-frequency recharge in the x, y, and
z directions of the space. The coils, generating a constant
magnetic field inside the volume they encompass, provide
wireless recharging of the ECOGIW-16E device, allowing
freedom of movement and avoiding any constraint to the
monkey. Cage details are available in Table 1.
Both the ECOGIW-16E device and the recharging cage
are wireless systems. This novelty introduces several improvements in experimental settings researching sensorimotor cortex functions. In typical wired systems, the
cables need to be protected from the hands of the primates
because they typically try to strip them away. To avoid this
problem, behavioral experiments require that the monkey
sit in a special chair that does not allow the animal’s arms
to reach the cables. Our cable-free system therefore opens
a new window of opportunity to observe the neural activities in unrestrained, freely moving animals. Using the
smart wireless recharge cage, it is possible to recharge
the implanted device during the physiological rest period
while recording the ECoG signals at the same time.
Electrophysiological Measures
In this study, we used commercial software for ECoG
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P. Romanelli et al.

TABLE 1. Details of the recharging cage characteristics
Characteristic
Dimensions
 Weight
  External dimensions,
in mm
 Characteristics
Power supply
 Voltage
  Absorbed power
HF power unit
  Frequency
  Horizontal coils (no.)
  Vertical coils (no.)
  Max magnetic field

Measure
450 kg
920 (width) × 1700 (length) × 2000
(height)
ETS 123
230 VAC
1200 W
1000 kHz
3
3+2
163 A/m IEEE C95.1

ETS = European Treaty Series (European Convention for the Protection of
Vertebrate Animals Used for Experimental and Other Scientific Purposes); HF
= high frequency; IEEE = Institute of Electrical and Electronics Engineers; max
= maximum; VAC = volts of alternating current.

recording (Micromed), and we tested software specifically
developed for our hardware (Aethra Telecommunication
Co.) for DCS and impedance measurement. The ECoG
recording is done using the previously described customized cage with the animal fully awake and in freely moving condition. A video recording was synchronized with
ECoG. Impedance checks of each contact preceded the recording and consisted of electrochemical impedance spectroscopy of each electrode performed using AB MEDICA
internally developed software. It is possible to set up electrochemical impedance spectroscopy from 1 to 250 Hz for
each electrode. Moreover, the motor evoked potential was
obtained by DCS of cortical electrodes coupled to a video
recording of the motor response, with the animal anesthetized. We achieved cortical stimulation using embedded
capabilities of the implant by sending electrical pulses to
each electrode at constant voltage (3 V at 1–2 mA). We
registered median and tibial nerve somatosensory evoked
potentials (SSEPs) once a week after induction of general
anesthesia outside the recording cage, inside a dedicated
mobile ECoG unit.
We briefly describe the SSEP protocol: the nonhuman
primates were anesthetized using a mixture of ketamine
(7 mg/kg) and xylazine (0.6 mg/kg) administered intramuscularly, and then put onto a comfortable table that was
covered with an absorbent sheet. The median nerve area at
the level of the wrist and the tibial nerve area at the level
of the ankle were shaved, and 2 needle electrodes were
placed following the nerve trajectory. A pulse generator
(Energy Light; Micromed) provided a bipolar electrical
stimulation to the nerve (stimulation parameters: 1 Hz, anode proximal, cathode distal, pulse width 125–250 μsec,
amplitude variable). The generator was synchronized to
the ECoG recording software. When the nerve stimulation
was performed, it was possible to record the related cerebral signal in correspondence to the somatosensory area.
This procedure was done several times, to identify exactly
4

J Neurosurg  May 11, 2018

TABLE 2. Description of the 3 stimulation protocols
Stimulation Protocol
No. 1
  Electrode no.
 Impedance
 Shape
  Frequency
  V positive
  V negative
  Pulse width (tp = tn)
 Tpn
No. 2
  Electrode nos.
 Impedance
 Shape
  Frequency
  V positive
  V negative
  Pulse width (tp = tn)
 Tpn
No. 3
  Electrode nos.
 Impedance
 Shape
  Frequency
  V positive
  V negative
  Pulse width (tp = tn)
 Tpn

Value
4
4 KW
Bipolar
1 Hz
3V
3V
100 μsec
5 μsec
4, 5, 7, 13
4, 3.8, 5, 5 KW
Bipolar
7 Hz
3V
3V
500 μsec
5 μsec
4, 5, 7, 13
4, 3.8, 5, 5 KW
Bipolar
30 Hz
3V
3V
500 μsec
5 μsec

Tn = negative time; tp = positive time; tpn = time between positive and negative
component.

which electrodes more frequently record the resulting signal to the stimulation. We identified electrodes 4, 5, 7, and
13. We used data derived from this study phase to develop
the DCS stimulation protocols (Table 2).
Tissue Preparation and Histological Analysis of Brain
Reactivity
Thirty weeks after implantation, the monkey was perfused transcardially with 0.9% NaCl followed by 10%
formalin, as previously described by our team.28 To avoid
damaging the brain tissue during histological procedures,
the monkey brain—including the device and the skull—
was fixed in 4% formalin. After fixation, we removed the
device carefully to test its adhesion to the brain cortex.
Then, the brain was removed from the skull and postfixed
overnight in the same fixative. Next, we placed the brain
in phosphate-buffered saline with the addition of 30% sucrose until the brain sank. Before freezing, we cut the brain
to form a block, and both cerebral tissue and fibrotic tissue covered the implant. Furthermore, we investigated the
control tissue. Subsequently, the brain was serially coronally sectioned using a freezing microtome. Sections were

P. Romanelli et al.

FIG. 3. ECoG recordings in awake monkey at 24 hours, 3 months, and 6 months after implantation. Electrophysiological recordings were obtained using wireless transmission in the plastic cage.

collected and processed for Nissl and Perls iron staining
(RAL Diagnostics), and immunohistochemistry analysis
for glial fibrillary acidic protein (GFAP), vimentin (Vim),
and ionized calcium-binding adapter molecule–1 (Iba-1).
We incubated sections with the following primary antibody solutions overnight at 4°C, including GFAP (1:500,
polyclonal rabbit IgG; Dakocytomation) to identify astrocytes; Vim (1:500, monoclonal mouse IgG; Dakocytomation) to identify meningeal-derived fibroblasts; and Iba-1
(1:500, polyclonal rabbit IgG; Wako Chemicals GmbH) to
identify macrophage and/or microglia. Secondary antibodies were diluted, including goat anti–rabbit IgG (Alexa
488; Molecular Probes) for GFAP and Iba-1. All sections
were counterstained by incubation with the nuclear dye
propidium iodide (Sigma). Sections treated only with secondary antibody but with no primary antibody were used
to determine nonspecific binding. Tissue sections were
mounted with Fluorsave, and bound primary antibodies
were visualized on a confocal microscope.

Results

Prolonged Wireless ECoG Recording
The procedure and postoperative course were uneventful. The monkey recovered immediately and was able to
resume all normal motor activities (walking and climbing
into the cage and feeding unassisted) within a few hours.
The ECoG signals of the 16 electrodes were recorded at a
512-Hz sampling rate and a software-imposed band-pass
filter from 0.008 to 400 Hz. We first removed all frequencies below 0.5 Hz from the ECoG signals by using a highpass filter. The ECoG signals were acquired every day for
6 months and remained stable during the study. Figure 3
shows 3 screenshots of EcoG signals: a few hours after the
implant, after 3 months, and after 6 months. Electrode impedance values remained at 40 KW, below the acceptable
threshold of 100 KW. We also computed the fast Fourier

transform of the ECoG traces. The power spectral estimate
is based on the Welch method applied to a centered signal,
1-second window analysis, with an overlapping 750 msec,
and each section is provided with a Hamming window.43
The frequency spectrum shows the characteristic decrease
in amplitude at higher frequencies and all the characteristic frequency components of an ECoG signal. Spectral
analysis of the averaged signal showed the expected power
reduction in all frequencies between the first and the last
month of observation, due most probably to the thickening
of fibrotic tissue surrounding the implant.8,13
In addition, we performed a spectral analysis in each
channel and evaluated the amount of line noise in our
ECoG signal. For each electrode, we calculated the relative power of the 50-Hz line noise band (P49,50) over the
total power (P0,250), giving rise to the percentage of electronic noise in each channel (P49,50/P0,250). The percentage
of electrical interference in total signal for each electrode
was stable at < 5% during the 6 months of the study. Only
at the final recording did electrode 10 increase to more
than 10% of electrical noise, probably due to a dysfunction
of the specific electrode.
We measured values of impedance at different frequencies (from 16 Hz to 250 Hz) in all channels. In Fig. 4 we
report impedance values for each electrode (1 kHz), and
the inset graphic shows the relative mean value. During
the entire duration of the study, impedance values had remained well below the threshold of 100 KW (red line in
Fig. 4), representing the limit of the impedance over which
signal quality becomes poor. Our device has impedance
values consistent with the ones found in the literature.21
Overall, the signal quality remained excellent for the
entire 6 months of recording, except for a modest degradation during the 1st week after the procedure (probably due
to postoperative debris), as well as during the last 3 weeks,
when the implant duration over the cortex drew close to 6
months.
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P. Romanelli et al.

FIG. 4. Graphs showing electrode impedance at 1 kHz over time. The mean impedance for each electrode during the total study
duration is shown. Figure is available in color online only.

We also performed throughput tests of the antennae
in the device. After the surgery, we measured the electromagnetic field in a not-anechoic room without known interferences. The electromagnetic field is almost symmetrical, even in the presence of unknown disturbances, and it
decreases with the distance from the device.
Somatosensory Evoked Potentials
We analyzed the evolution of the first component (N1 or
P1) of the SSEPs for the median and tibial nerve in the animal. We carefully inserted stimulator needles in the same
spot at each acquisition and used constant parameters capable of eliciting muscle contraction. We were able to follow the evolution of the SSEP over time. Also, by signal
inspection it was possible to localize the central sulcus and
the motor strip projection to the grid. This motor projection, represented by polarity changes in the first inflection
curve, was present during the 6-month period of observation (Fig. 5).
Time delays between the nerve stimulation and the related recording of the signal remained constant throughout
the 6-month experiment (median nerve: N1/P1 was 16.64
± 3.16 msec; tibial nerve: N1/P1 was 22.43 ± 1.07 msec).
In contrast, curve amplitude (in μV) was significantly reduced for tibial nerve SSEP (from 135.42 to 56.50 μV, p
< 0.0001) but not for median nerve SSEP (from 19.60 to
13.82 μV, p = 0.0739; Wilcoxon matched-pairs signedrank test) between 7 and 181 days of observation (Fig. 6).
Direct Cortical Stimulation
Finally, we performed DCS to test the device stimulation features and functionality. We used 3 different stimulation protocols. After careful stimulation in each electrode, we found that it was possible to elicit contralateral
arm movements by using the first and third stimulation
protocols (Table 2). Protocol 1 in electrode number 4 produced thumb flexion, and protocol 2 in the same electrode
6

J Neurosurg  May 11, 2018

provoked not only right thumb but also elbow complete
flexion. Protocol 3 was able to reproduce finger flexion in
electrode number 5.
Long-Term Biocompatibility Evaluation
Histological examinations were performed postmortem,
30 weeks after implantation. The cortex was inspected
carefully to assess macroscopic signs of damage caused by
the prolonged contact of the grid; visual inspection failed
to show macroscopic signs of tissue defect. Observation
of the implantation site showed a slight brown pigmentation of the brain surface under the grid, probably due to
resorbed bleeding. The brain site underlying the electrode
array showed its integration into a newly formed dural layer. This neoformed tissue (NT) appeared to be continuous
to the constitutive dura mater. We observed no adhesion
between the newly formed connective tissue covering the
grid and the cortical surface; the grid was easily removed
without damaging the cortex.
Immediately after explantation, the grid was extracted
from the surrounding dural layers. Some of the exposed
electrodes revealed cracks and wrinkles on the surface.
We analyzed the dural layers and grid under the stereomicroscope to assess histological features of reactive dural
tissue and to observe the electrodes’ mechanical condition
(Fig. 7).
Observation of a capsule transversal section revealed a
connective tissue formation on two sides of the electrode
array (Fig. 8A). The thickness of the reactive tissue ranged
between 450 μm (inner layer) and 800 μm (outer layer)
(Fig. 8B–D). We observed in Fig. 8B and C that the dural
scar (reactive dura mater) was interfacing with the outer
layer of NT. As shown in Fig. 8C and D, Perls iron staining
revealed hemosiderin in the reactive tissue, suggesting an
old hemorrhage in these areas. Note that the thickness of
the constitutive dura mater is approximately100 μm after
tissue preparation.

P. Romanelli et al.

FIG. 5. A: Example of median nerve SSEP response of the 15.9 × 11.5–mm ECoG grid. The diameter of the recording sites was
1.09 mm and the electrode pitch was 2.99 mm. Change in polarity can be perceived between electrodes 4 and 5, where dipolar
deflections at 13 msec were seen (horizontal black arrowheads). These changes signal the presence of the central sulcus between
those electrodes. (Data averaged 156 repetitions, and the vertical black arrowhead designates the trigger mark.)  B: Electrode
grid position showing the central sulcus (white line). The blue area corresponds to the premotor cortex (positive early deflections),
and the red area corresponds to the sensitive strip.  C: Cortical stimulation before grid implantation: the position of maximal hand
contraction is shown below the fork probes (Inomed Cortical Probes). Figure is available in color online only.

We performed immunohistological analysis to better
assess features of the reactive tissue encapsulating the grid.
Figure 9 shows representative GFAP, Iba-1, and Vim expression patterns in the capsule. As shown in Fig. 9B, the
reactive tissue surrounding the electrode array did not contain any GFAP-positive cells, indicating the absence of astrogliosis in the capsule. Adjacent sections used Iba-1 and
Vim antibodies to label microglial cells and meningeal fibroblasts, respectively, and this showed that reactive tissue
contains homogeneously activated microglial cells with an
increased density in hemosiderin-containing areas (Fig.
9D), suggesting a recruitment of microglial cells for hemosiderin elimination. As shown in Fig. 9E, we observed
Vim-positive cells in the NT with a higher protein level
in the outer layer, outside of hemosiderin deposits. This
result suggests that meningeal-derived fibroblasts migrate
into the reactive tissue from the meningeal space and contribute to the foreign body response. These results clearly
show the well-known characteristics of encapsulation for
subdural implantation of electrode arrays, with microglial
and fibroblastic components.
The last part of the histological investigation was conducted to evaluate brain cortex reaction beneath the electrode array and to detect signs of inflammation. We performed Perls iron staining to detect signs of alteration and
old hemorrhage. No sign of cortical damage was found
over the region covered by the grid, except in a single point

where repeated stimulation was performed; this was not
representative of the stimulated area. As shown in Fig.
10C and E, a small region of cortical damage (diameter <
1 mm) can be identified under electrode number 4, which
was used for multiple mapping procedures.47
During the electrical stimulation, we adopted all precautions to limit or avoid damage to the brain tissue. Shannon’s equation has proved the empirical relationship be-

FIG. 6. Bar graph showing the mean variation in amplitude of the first
component (N1/P1) of SSEP in the tibial and median nerves. The ECoG
microelectrodes record a significant reduction in amplitude in tibial
SSEP but not in median SSEP. Encapsulation could attenuate potential
amplitude more when the source is far from the recording electrode
(ankle stimulation) than when the source is below the electrode grid
(hand). ***p < 0.0001.
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P. Romanelli et al.

FIG. 7. A: The monkey brain after 30 weeks of contact with the electrode array. The dotted lines delimit the contact area between
the brain cortex and the electrode array.  B: Electrode array explanted after 30 weeks, embedded in a newly formed dural layer.
Ant. = anterior; Lat. = lateral; Med. = medial; Post. = posterior. Figure is available in color online only.

tween charge delivered to the tissue and tissue damage.37 It
has been considered that K = 1.7 with a phase of 500 μsec,
the electrode has a 1-mm pad made of platinum, and the
maximum current that can be delivered while still avoiding damage to brain tissue is 3.4 mA.11 As shown in Fig.
4, the mean impedance value on electrode number 4 is 10

KW and, considering the battery voltage of 3 V, the maximum current delivered on electrode number 4 is less than
1 mA—well under the maximum value of 3.4 mA.
We performed an analysis of cortical GFAP expression
in electrode array–covered and electrode array–uncovered
brain cortex areas and noted that expression of the astro-

FIG. 8. Macroscopic and microscopic views of the encapsulated electrode array (EA).  A: Photograph of the electrode array
embedded between NTs on top and below.  B: Histological slice showing constitutive dura mater (CDM) and reactive dura mater
(RDM) covering the NT. Nissl staining.  C: Histological slice showing hemosiderin deposits into the NT. Perls iron staining.  D: Histological slice showing hemosiderin deposits into the NT. Perls iron staining. Figure is available in color online only.
8

J Neurosurg  May 11, 2018

P. Romanelli et al.

FIG. 9. A: Photograph of the electrode array (EA) embedded between NTs on top and below.  B: Representative GFAP expression pattern (green) in the reactive tissue around the electrode array. The reactive tissue showed no GFAP antibody staining.  C: Representative Iba-1 expression pattern (green) in the reactive tissue around the electrode array. Microglia is positively
marked in all the NT, with a higher density of microglial cells in areas containing hemosiderin deposits.  D: Representative Vim
expression pattern (green) in the reactive tissue around the electrode array. The outer layer of reactive tissue (in contact with the
reactive dura mater [RDM]) shows a higher Vim level. Bar = 200 µm (B–D). Figure is available in color online only.

cyte marker was highly concentrated in the glia limitans.
In electrode array–covered brain cortex, we observed a loss
of continuity for the glia limitans and reactive astrocytes
in the cortex in the spot where the cortical surface was altered. In some areas, the thickness of electrode array–covered glia limitans was increased because of the proliferation of reactive astrocytes. GFAP staining revealed a mild
astrogliosis in the cortex under the electrode array. The
Iba-1 immunostaining (Iba-1 expressed by microglia and
macrophages) showed the absence of activated microglial
cells into the control brain cortex after 30 weeks (Fig. 11).
Observation of the electrode array–covered brain cortex
showed the presence of activated microglial cells into the
reactive glia limitans and into the brain cortex under the
electrode array after 30 weeks. Note that expression of the
microglial marker is highly concentrated in the reactive
glia limitans and in the first cortical layer. These results
suggest that the electrode array induced localized and
mild brain tissue response after a 30-week period.

Discussion

A detailed prospective analysis of the reliability of a
long-term wireless ECoG device implanted on the sensorimotor cortex of a nonhuman primate is reported. The
evaluation tested not only the wireless transmission and
the quality of the signal, but also the daily impedance of
each electrode, as well as the elicitation of SSEPs and the
motor effects of DCS. This neuroprosthesis also provides

wireless recharging within a dedicated primate cage, allowing a constant battery charge in freely moving animals.
Furthermore, we evaluated the biocompatibility of the entire neuroprosthesis, including not only the subdural grid
but also the wireless case implanted on the skull near the
craniotomy.
The implantable wireless device presented here allowed
us to perform prolonged ECoG recording and DCS for 30
weeks. Long-term wireless ECoG recording was possible
in a noisy, nonisolated environment, in a freely moving
animal. The ECoG signals recorded a power reduction at
6 months, which was explained by local dura mater neoformation. The ECoG signal quality remained excellent
throughout the experiment, with low impedances observed.
The device was removed easily at the end of the 30 weeks
of observation. Encapsulation was partially responsible for
attenuation in the tibial SSEP signal. The median SSEP
signal was stable, probably due to the distance between the
source of SSEP and the microelectrodes (the grid, after sensorimotor cortex mapping, was implanted directly over the
cortical hand representation). Line noise was maintained
below 5% of the total signal throughout the experiment,
giving an indirect measure of stable impedance changes
of the electrode-tissue interface. We found no adhesion between the device and the cortex. The cortex underlying the
implanted grid showed no macroscopic signs of damage.
Immunohistochemical analysis revealed mild superficial
astrogliosis, moderate microglial activation, and mild resorbed bleeding under the electrode array. Overall, the neuJ Neurosurg  May 11, 2018

9

P. Romanelli et al.

FIG. 10. A: Photographs of incomplete brain coronal sections showing contact areas of the electrode array (EA) with the cortical
surface and the control side.  B: Representative histological slice demonstrating the absence of cortical defect on the control
side.  C: Representative histological slice demonstrating alteration of the brain cortex under the electrode array. Hemosiderin deposits are stained in blue (arrow).  D: Representative histological slice demonstrating the absence of cortical defect on the control
side.  E: Representative histological slice demonstrating alteration of the brain cortex under the electrode array. Hemosiderin deposits are stained in blue (arrow). Perls iron staining (B–E). Bar = 5 mm (B, C); 1 mm (D, E). Figure is available in color online only.

roprosthesis was well tolerated, considering the extended
implantation time. The dural encapsulation of the grid is,
in our view, not a matter of concern in humans: the dural
neoformation seen here is peculiar to nonhuman primates,
which typically show very intense neodurogenesis following dural opening. A similar phenomenon is very unlikely
to be seen in a clinical context.
The possibility shown here to greatly extend the implantation time of a subdural grid paves the way for prolonged
ECoG recording during epilepsy surgery, thus improving the chances of localizing the epileptogenic focus and
extending the range of patients to whom invasive ECoG
recording can be offered. This device, which provides a
bidirectional interface well tolerated over a long time, also
lends itself to further developments toward closed-loop seizure control and BCI applications.
Epilepsy has been addressed in recent years by brainmachine interfaces, with the main objective of detecting
seizures and transmitting an alert to patients.12 One category of epilepsy alert devices is noninvasive wearable devices, providing a fast response to ongoing seizures of the
tonic-clonic type, based on accelerometers (Epilert: https://
bio-lert.com; Smartwatch: https://smart-monitor.com/
about-us/news-events/). More closely related to our applications are the invasive seizure detection systems, integrating an ECoG signal. They can detect seizures and transmit
an alert to the patients before secondary generalization oc10

J Neurosurg  May 11, 2018

curs.12 Some of them can be coupled to an electrical stimulator, delivering electrical pulses to therapeutic targets (i.e.,
anterior thalamus) when seizures are detected.40 However,
these devices are not suitable for presurgical evaluation of
epileptic patients: they have very low spatial resolution due
to electrode characteristics (low number, pitch, and long
diameter). There is no recording and stimulating device for
presurgical epilepsy evaluation that is similar to the prototype presented here. Furthermore, the device proposed
here is a preliminary proof of concept developed for primate surgery. Another device providing similar long-term
recording and wireless transmission and recharging is
currently being tested in animal models, in anticipation of
clinical application.
Patients with drug-refractory epilepsy could greatly
benefit from prolonged wireless recording, allowing them
to reduce the risk of intracranial infections proceeding
along the intracranial cables. Prolonged wireless ECoG
recording could be offered to a substantial population of
patients affected by nondaily or episodic seizures. As of today, this patient sample is not a surgical target, because the
short implantation time of conventional wired intracranial
recordings added to the surgical stress and effects of anesthesia does not allow time enough to record and localize
the epileptogenic focus. In such cases, a longer period of
observation could help to identify the epileptogenic focus
and increase the accuracy of the resection.

P. Romanelli et al.

FIG. 11. Representative Iba-1 expression patterns in electrode array–uncovered brain cortex (A) and electrode array–covered
brain cortex (B and C). Bar = 20 µm. GL = glia limitans (arrows). Figure is available in color online only.

Some potential barriers preventing the clinical use of
a device implanted over a long period are signal attenuation over time, foreign body rejection, and development of
subdural hematomas. Moreover, a much larger recording
surface than that offered by this proof-of-concept device
will be necessary for clinical applications in epilepsy surgery. We are currently engaged in the preclinical testing of
a device providing 128 channels spread over a thin-layer
silicone grid (thus aiming to prevent the development of
subdural hematomas while providing a large recording
surface that can be tolerated over multiple weeks). The
results of these preclinical studies are rather encouraging
and will be reported soon.
We have developed and tested a 128-channel device because this represents the best compromise between sample
rate and radio band used. Our device transmits to 400 MHz
according to the MICS specification. The MICS band was
created by the Federal Communications Commission specifically to allow the safe use of implanted wireless devices
for diagnostic and therapeutic applications. The frequency
used reduces the risk of interference with other devices
and requires a transmission power limited to 25 mW. Doubling the number of channels (256) would imply reducing by half the sample rate and the quality of the received
signal. Therefore, it is technically possible to increase the
number of channels, but the drawback is the detriment to
the quality of the acquired signal, and therefore to the possibility of making an adequate diagnosis.
A wireless long-term system can provide recordings of
previously undetectable seizures because of the longer observation period. Current systems of invasive EEG (i.e.,
stereo-EEG) are limited to 7–15 days of exploration, with
cable and extensions passing through the skin. The risks of
infection are reduced in a completely closed system. One
can also imagine a home system, which does not require
hospitalization and dedicated medical personnel.
Currently, most ECoG BCIs have an electrical connector that passes through the skull and skin.22,36,45 This is not
a practical solution for long-term implantation. The challenge has been to improve the next generation of implantable devices by making them wireless, with a large number of electrodes and long duration of functionality. Wireless interfaces are beginning to emerge; e.g., Vansteensel
et al.41 have described a first wireless ECoG implantation
in a locked-in syndrome secondary to amyotrophic lateral
sclerosis. The fully implanted BCI consisted of 4 commer-

cially available subdural electrodes (4 electrodes on each
strip; each electrode was 4 mm in diameter, and there was
a 1-cm interelectrode distance) placed over the motor cortex and a transmitter (Activa PS) placed subcutaneously
in the left side of the thorax. Only 2 strips are connected
to the implantable pulse generator, making accessible 8
electrodes to wireless bidirectional transmission. This is
a very promising approach that has the merit of being almost ready for clinical use (the Activa PS transmitter is not
commercially available yet), but interelectrode distance
and only strip geometry for electrodes may be an issue if
used for epilepsy surveillance and cartography.
Su et al.39 introduced a compact implantable wireless
32-channel bidirectional brain-machine interface (BBMI)
to be used with freely moving primates. It is a more dedicated device with stimulation and sensing characteristics,
but it still uses intracortical electrodes (Utah array) as the
neural interface, which is not suitable for epilepsy exploration. The Nicolelis group has also published some wireless
interface data obtained in monkeys,33 allowing the animal
to pilot a wheelchair. The device used a Utah array, and
the wireless portion of the implant is exposed in a case not
covered by skin. This makes the device not suitable for
long-term implantation.
Other BCI implants, some of them shown in Table 3,
are at different technological levels of readiness and are
not suitable for presurgical epilepsy evaluation. The Neurochip-2 is a device conceived to be placed in an external
chamber in the primate’s head and to have only offline
recording and stimulation.46 The WIMAGINE (Wireless
Implantable Multichannel Acquisition System for Generic
Interface with Neurons) is a fully implantable ECoG device that is in the early stages of clinical testing for use as
a BCI in tetraplegic patients, but lacks an electrical stimulation module.27 The PennBMBI (brain-machine-brain
interface) is a device with 4 recording and 2 stimulating
electrodes with a high sampling rate, designed for closedloop BCI, not suitable for the large-area investigation necessary in epilepsy surgery.24 The W-HERBS (Wireless
Human ECoG-based Real-time BMI System) device has
a multielectrode matrix (64 electrodes) for recording large
cortical areas, but has no stimulation module. Nguyen et
al.29 have advanced a recording system that combines a
32-electrode matrix with optical stimulation, but it is not
wireless, requiring a wired connection for signal transmission. Angotzi et al.2 have developed an interesting device
J Neurosurg  May 11, 2018

11

P. Romanelli et al.

TABLE 3. Literature review of recently developed wireless implantable devices and comparison of their features
Feature

Su et al., 2016

Recording
channel
ADC resolution

Zanos et al., 2011;
Neurochip-2

Sauter et al., 2015; Liu et al., 2015;
WIMAGINE
PennBMBI

Hirata et al., 2012; Nguyen et al.,
W-HERBS
2014

Angotzi et
al., 2014

32 unipolar/
bipolar
16 bits, 800 SPS/
channel, up
to 30 kSPS/
channel
Sampling rate
0.1–20 kHz
Bandwidth
24-GHz RF communication
link w/ mESB
protocol
Communication Rechargeable

3 unipolar/bipolar

64

4

64 × 2

32

8 bits, 256 SPS

12 bits, 1 kSPS

12 bits, 21
kSPS

12 bits, 1 kSPS

10 Hz–7.5 kHz
Serial cable/infrared
data link

0.5–400 Hz
Proprietary UHF
link in MICS
band

0.05 Hz–6 kHz 0.1 Hz–1 kHz
Communication Bluetooth
link, 2.4-GHz
RF

16 bits, 400 8 bits, 15
kSPS (12.5
kSPS/
kSPS/
channel
channel)
0.2 Hz–5 kHz 1 Hz–10 kHz
Wired
2.4-GHz
ISM band

1 or 2 rechargeable

Inductive link

Rechargeable

Power supply
Power consumption

3.7-V battery
284–420 mV

NA
3.7-V battery
3.7-V ion battery
75 mW w/o charg- 7.3-mA transmit 4.9 mW (AFE), 300
ing, 350 mW w/
for sensor
mW (wireless)
charging
node only
NA
NA
Wireless charging,
4-W coil at 38mm distance
31 × 13 × 8
8-mm thickness,
50-mm diam,
mm, 43 × 27
40-mm diam, 60
antenna 10 cm2,
12.54-mm thick× 8 mm, 56 ×
× 60 × 8 mm, 20
ness
36 × 13 mm
× 30 × 2.5 mm

2


3.6-V battery
4.22–15.4 mA

Battery charging Wireless ultraNA
sonic charging
Size

35-mm diam

Stimulation
channel
Stimulation
voltage
Current density

4 unipolar/bipolar 3 unipolar/bipolar
20 V

63 × 63 × 30 mm

15 V (normal), 50 V
(high V)
40-µA pulse
10–200 µA current
or 0.5–5 mA
Pulse width
1 msec minimum 0.2, 0.6 msec
NA
Pulse frequency 250 Hz
1 min or 1 min 10 sec NA

Polymer lithium



12 V





0–1 mA



200 µsec
NA

NA
NA

8

5-V USB
NA


3.7 V, 700
mA/hr
NA


NA



29.5 × 43.4
mm

NA

1 optical
stimulus


8 bipolar


NA
NA

9V
300 µA
NA
NA

ADC = analog-to-digital converter; AFE = analog front end; diam = diameter; ISM = Industrial, Scientific, and Medical; NA = not applicable; RF = radiofrequency; UHF =
ultrahigh frequency; mESB = micro Enhanced ShockBurst (a wireless protocol, Nordic Semiconductor); — = not done or no information.

for small animals that is completely wireless, with 8 recording channels and 8 stimulating electrodes based on
nonrechargeable batteries.
Considering the size of the primate brain, we developed
a proof-of-concept device that allowed long-term ECoG
recording over 6 months. On the basis of this experience,
we then developed a 128-channel wireless subdural grid,
which has been tested on suitable animal models (pigs) to
proceed to human implantation. The recharging process in
human applications is meant to develop a recharging modality that permits patient movements. For this reason, we
created a portable wireless recharging system, which works
through an external coil. The implanted device is supplied
by medical-grade–certified batteries, in a titanium case. By
using a cap with a large area covered in Velcro that is worn
only during the recharging phase, the external coil could
be coupled with the area corresponding to the implanted
device. Attaching the wireless recharger to the implantation area allows electromagnetic coupling between the coil
12

J Neurosurg  May 11, 2018

integrated into the implanted device and the one integrated
into the wireless recharger; in this way, power transfer can
start. The external coil could be fixed by a headset cover,
to guarantee its stability. The wireless recharger provides
visual and auditory signals: a bicolor light-emitting diode
becomes red to signal some errors in the recharge phase.
If no errors occur, the light-emitting diode becomes green
to give feedback about the state of recharge. An auditory
signal indicates the joining between the two coils, so that
the recharge phase can start.
The management of charge current requires a scientific
rationale and adherence to ISO guidelines (ISO 14708–1
specifies requirements for establishing control and protection mechanisms), to prevent harm to the patient caused
by heat. The ICNIRP (International Commission on NonIonizing Radiation Protection) guidelines for limiting
exposure to time-varying electric, magnetic, and electromagnetic fields1,23 report that exposure to magnetic and
electrical fields and the relative energy absorbed by the

P. Romanelli et al.

human body (i.e., the SAR [specific absorption rate]) have
to be controlled by considering the tissues’ heat elevation.
A heat elevation of 1°C–2°C from the baseline does not
involve tissue damage. Some authors25,44 propose thermal
considerations regarding heat’s effects on neuroimplanted
devices. They confirm the limit of +2°C (approximately
39°C), beyond which tissue damage and cell necrosis could
occur. A 2°C increase occurs within approximately 1 hour
of charging, so they suggest caution in the management of
charging time. Because of this, we created a control mechanism consisting of 1) an internal microprocessor measuring temperature, 2) an external thermal protection, and 3)
a timer. The temperature and time of the recharge phase
can be set by using the application software. The internal
microprocessor interrupts the recharge phase in the event
that the temperature exceeds the determined value, or in
case the recharge time exceeds the determined value. The
external temperature sensor measures degrees by the skin
of the skull, providing a further temperature protection
tool, which is independent of the internal microprocessor.

Conclusions

The novel wireless ECoG device described in this work
as a proof of concept provides an excellent platform for
prolonged ECoG recording. Potential clinical applications
include BCI and epilepsy surgery. In the latter case, the
absence of subcutaneous cables allows prolonged monitoring, thus enhancing the chances of achieving seizure focus
localization. Moreover, it offers a prospect to treat a large
subset of patients with drug-refractory epilepsy who have
nondaily seizures and rarely undergo invasive monitoring
due to the low likelihood of registering and localizing an
ictal focus over a short time. Based on this experience, we
are now testing a 128-contact wireless device suited for human use.

Acknowledgments

We express our gratitude to Dr. Chiara Fornoni for the valuable
editorial assistance.

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Benabid AL, Biella GE: A novel wireless recording and stimulating multichannel epicortical grid for supplementing or
enhancing the sensory-motor functions in monkey (Macaca
fascicularis). Front Syst Neurosci 9:73, 2015

Disclosures

AB MEDICA S.p.a. manufactured the ECoG device prototype
and also funded the entire project, including materials and structures, with the declared aim to test the in vivo operation and the
biocompatibility and device reliability during implantation. Pantaleo Romanelli is a consultant for and Cosimo Puttilli and Mauro
Picciafuoco are employees of AB MEDICA S.p.a. Also, ATLC
S.r.l., a company of the AB MEDICA group, partially cofunded
(in the percentage of one-third) Marco Piangerelli’s doctoral
scholarship.

Author Contributions

Conception and design: Romanelli, Benabid, Torres. Acquisition of data: Romanelli, Ratel, Gaude, Costecalde, Puttilli, Picciafuoco, Benabid, Torres. Analysis and interpretation of data:
Piangerelli. Drafting the article: Romanelli, Ratel, Gaude, Costecalde, Puttilli, Benabid, Torres. Critically revising the article:
Piangerelli, Gaude, Costecalde. Reviewed submitted version of
manuscript: Romanelli, Ratel, Puttilli, Picciafuoco, Benabid, Torres. Approved the final version of the manuscript on behalf of all
authors: Romanelli. Statistical analysis: Piangerelli, Picciafuoco.

Correspondence

Pantaleo Romanelli: AB MEDICA S.p.a., Milan, Italy.
radiosurgery2000@yahoo.com.


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