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Next-Generation Closed-Loop Neural Interfaces: Circuit and AI-driven

innovations

Article in IEEE Solid-State Circuits Magazine · November 2024

DOI: 10.1109/MSSC.2023.3309782

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 Mahsa Shoaran

Next-Generation
Closed-Loop
Neural Interfaces
Circuit and AI-driven innovations

N
eural interfaces have
opened new fron-
tiers in neurology
and neuroscience,
offering possibili-
ties for understanding the brain and
developing therapeutic devices to
restore or replace lost functions.
Among these interfaces, the closed-
loop systems, including both inva-
Digital Object Identifier 10.1109/MSSC.2023.3309782
Date of current version: 14 November 2023
sive and noninvasive neurostimulation
technologies and brain–computer inter-
faces (BCIs), hold great promise for real-
izing these goals. Closed-loop systems
continuously monitor and modulate
neural activity in real time, enabling
precise control and targeted inter-
vention for symptom management,
movement restoration, or other ther-
apeutic purposes. ­ Moreover, closed-
loop neuromodulation is expand-
ing the capabilities of peripheral and
spinal cord interfaces, improving sen-
sorimotor function recovery and en-
hancing prosthetic control.
Closed-loop neuromodulation sys-
tems and BCIs combine knowledge
from neuroscience, engineering,
and computer science to facilitate
real-time, bidirectional interaction
between the brain and implantable,
wearable, or assistive devices. Based
on the modality of neural signals and
the intervention approach, these tech-
nologies can be categorized into non-
invasive and invasive systems. In the

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Closed-loop neuromodulation systems and
BCIs combine knowledge from neuroscience,
engineering, and computer science to facilitate
real-time, bidirectional interaction between the
brain and implantable, wearable, or assistive
devices.
past decade, the neuromodulation and
BCI fields have witnessed significant
growth in both academic and indus-
trial sectors [1], [2], [3], [4]. Neverthe-
less, their clinical ­impact has remained
relatively limited to date. This is par-
tially due to the intricate nature of
the human brain, challenges in device
translation and validation, concerns
on long-term reliability, and the lack of
technologies with high efficacy needed
for widespread use. Overcoming these
challenges requires technological ad-
vancements, interdisciplinary collabo-
rations, and extensive clinical studies
to unlock the transformative potential
of neural interfaces for widespread
clinical applications.
Invasive and Noninvasive
­Neurotechnologies
Table 1 summarizes the neural re-
cording and stimulation modalities
used in both invasive and noninva-
sive neurotechnologies, highlighting
their advantages and disadvantages.
Currently, invasive ­neuromodulation
strategies based on electrical stimula-
tion, such as deep brain [4] and cor-
tical [5] stimulation, have emerged
as promising therapeutic options
for a wide range of brain disorders,
TABLE 1. COMPARISON OF INVASIVE AND NONINVASIVE NEUROTECHNOLOGIES FOR NEURAL RECORDING
AND NEUROSTIMULATION.
SENSING MODALITY
Invasive AP, ECoG, LFP, stereo-EEG
Noninvasive EEG, fNIRS, subscalp EEG
AP: action potential; DBS: deep-brain stimulation; ECoG: electrocorticography; EEG: electroencephalography; fNIRS: functional near-infrared
spectroscopy; LFP: local field potential; tDCS: transcranial direct current stimulation; TI: temporal interference; TMS: transcranial magnetic stimulation;
US: ultrasound.
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including medication-resistant epi-
lepsy, dystonia, essential tremor, and
obsessive-compulsive disorder (OCD),
among others. While optogenetics
has shown great promise in animal
studies, its translation to human and
clinical applications is still in its early
stages due to concerns related to ge-
netic modification of neurons and
associated ethical considerations. In
invasive neural interfaces, the sens-
ing modality for closed-loop feedback
may include high-resolution action
potentials, or lower-frequency signals,
such as electrocorticography (ECoG),
local field potential (LFP), and stereo-
electroencephalography (sEEG).
Conversely, there is an increasing
interest in developing noninvasive or
minimally invasive technologies for
individuals with milder neurologi-
cal or psychiatric conditions. These
approaches utilize wearable scalp or
subscalp EEG, functional near-infrared
spectroscopy [6], peripheral or be-
havioral measures for sensing, and
noninvasive methods like focused
ultrasound [7], transcranial magnetic
stimulation [8], transcranial direct
current stimulation, and temporal in-
terference [9] for brain intervention.
The aim is to deliver effective stimu-
STIMULATION TYPE
DBS, cortical, epicranial,
optogenetics
tDCS, focused US, TMS, TI
lation with reduced risks compared
to invasive methods and enhance pa-
tient convenience. However, noninva-
sive approaches face challenges, such
as low efficacy and limited spatial res-
olution. Additionally, these ­ methods
are often bulky, lack portability, and
involve complex setup and position-
ing. Given the predominant use of
invasive technologies in both com-
mercial and research-based closed-
loop systems, our focus in this article
will be limited to invasive interfaces.
Current and Emerging
­Neural ­Devices
The neuromodulation and BCI device
markets are expected to grow sig-
nificantly by 2030, driven by techno-
logical advancements, the increasing
incidence of neurological and mental
disorders around the world, and the
aging population. Key industry play-
ers like Medtronic, Boston Scientific,
and Abbott—as well as pioneering
neurotech companies and startups,
such as NeuroPace, Blackrock Neu-
rotech, Neuralink, Cortec, Synchron,
and Paradromics—are actively in-
volved in the development of BCI and
neurostimulation devices, with a fo-
cus on invasive systems (Figure 1).
The FDA-approved closed-loop
responsive neurostimulation (RNS)
­
system [5] analyzes ECoG signals from
up to four channels to detect and dis-
rupt seizures, by comparing a specific
epileptic “feature” against a predeter-
mined threshold. The AspireSR vagus
nerve stimulator by LivaNova is ca-
pable of dynamically adapting stimu-
lation based on changes in ictal heart
PROS CONS
High resolution, High Surgical intervention,
efficacy, invisible higher risk and cost
No major surgery, safe Low resolution, low
and accessible efficacy, obtrusive
 rate as a potential predictor of seizures.
Medtronic’s investigational Percept PC
and Summit employ spectral analysis
and a linear discriminant function with
a limited number of channels (four to
six) for stimulation regulation [10].
Newronika’s AlphaDBS (with CE mark
approval) utilizes simple biomark-
ers of targeted movement disorders
to adjust the stimulation parameters.
The investigational Picostim DyNeuMo
Mk-1 device is a cranial system that in-
corporates three-axis accelerometers
for inertial sensing and closed-loop
motion-adaptive neurostimulation [Fig-
ure 1(a)] [11].
In addition, we see an array of
neurotech startups in the BCI space,
as shown in Figure 1(b). For instance,
Blackrock Neurotech and Paradromics
develop devices that consist of small
silicon-based structures with multiple
microelectrodes that can be inserted
into specific brain regions, such as
the motor cortex. Since the first hu-
man implantation of Blackrock’s Utah
array in 2005, over 30 patients have
participated in ongoing clinical trials,
utilizing one or more implants to con-
trol prosthetic devices [1]. Paradromics
develops electrode arrays with thou-
sands of channels, enabling advanced
capabilities for high-resolution re-
cording and stimulation of neural ac-
tivity. The Neuralink devices consist
NeuroPace RNS
Blackrock Neurotech Synchron
FIGURE 1: (a) Closed-loop neuromodulation devices (commercially available and investigational) for epilepsy and movement disorders.
(b) Examples of neurotech startups and companies building invasive neural devices for BCI and neuromodulation.
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of thin and flexible electrode arrays
with over 1,000 channels, capable
of recording and stimulating electri-
cal activity at the level of individual
neurons. Precision Neuroscience de-
velops a flexible surface implant to re-
cord ECoG activity, while Synchron’s
stentrode is a minimally invasive tu-
bular metallic mesh with embedded
electrodes that adheres to cerebral
blood vessel walls to record popula-
tion-level neural activity [Figure 1(b)].
The Drive for Higher
Channel Counts
Notably, there is a shift toward the
development of neural interfaces
with substantially greater electrode
counts than those typically found in
commercial systems. Major contrib-
utors to this trend include Neuropix-
els, Neuralink, and Paradromics. The
imec’s Neuropixels probe prioritizes
fundamental neuroscience research
and the measurement of large-scale
brain activity, which explains its rel-
atively high power consumption and
lack of neuromodulation capability
[12]. In contrast, Neuralink and Par-
adromics strive to develop fully im-
plantable BCIs with potential clinical
applications, although specific neu-
rological indications have not yet
been defined. Achieving this goal
requires significant miniaturization
AspireSR VNS Medtronic Percept PC
(a)
Paradromics Neuralink
(b)
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and power reduction of neural inter-
face circuits compared to the exist-
ing designs [13], [14], integration of
closed-loop control strategies, and
addressing electrode safety and reli-
ability concerns in chronic settings.
These advancements are essential
for enabling the future clinical ap-
plication of these systems.
Closed-Loop Versus
Open-Loop Stimulation
While current therapeutic appli-
cations of neurostimulation pre-
dominantly employ the open-loop
approach, the most promising po-
tential lies in the development of
closed-loop or bidirectional technol-
ogies for optimal patient outcomes.
For instance, deep-brain stimulation
(DBS) has gained FDA approval as a
therapy for essential tremor, Parkin-
son’s disease (PD), epilepsy, OCD,
and dystonia [15]. However, the
conventional open-loop DBS in PD
leads to persistent side effects, such
as gait and speech impairments, as
well as psychiatric complications.
These issues primarily arise from
the continuous delivery of high-fre-
quency (~130 Hz) stimulation, dis-
regarding the dynamically varying
clinical state of the patients.
In a pioneering study [16], elec-
trophysiological biomarkers of PD,
AlphaDBS DyNeuMo
Flexible Leods
(x2)
Electrodes
(x4)
Implantable
Generator
Precision Neuroscience
apply. 43
 such as the beta-band power of LFP The adaptive DBS resulted in sig- less than half the energy and reduc-
within the 13- to 30-Hz range, were nificant improvements in patients’ ing speech side effects [Figure 2(b)]
utilized in an adaptive or closed-loop motor scores compared to continu- [16], [17]. Moreover, it demonstrated
manner to control DBS [Figure 2(a)]. ous stimulation, while delivering superior performance compared to
random intermittent stimulation.
Biomarker-driven closed-loop con-
trol has also found widespread ap-
Amplified, Digitally Filtered Over Beta
Band (13–30 Hz), and Thresholded LFPs plication in epilepsy [5], [18], [19],
where seizure biomarkers from
ECoG or intracranial EEG can trigger
stimulation for seizure prevention,
Stimulation Trigger as in the RNS device. Similarly, in
the context of Tourette’s syndrome
DBS and treatment-resistant depression,
DBS Trigger stimulation can be activated based
on features linked to tic onset [20] or
Beta Filtered LFP
mood state [21]. In general, closed-
(a) loop stimulation offers the potential
for more effective stimulation com-
pared to its open-loop alternatives,
∗
resulting in reduced side effects and
% Motor Improvement

∗
0 ∗ 80
improved energy efficiency, thereby
Speech Intelligibility

Speech
–20 extending the device’s battery life.

Deterioration
70 Baseline
–40
AI-Enabled Closed-Loop
60
–60 Neuromodulation
∗ Despite its advantages over open-
–80 50
cDBS aDBS Random Off DBS aDBS cDBS
loop stimulation, the simple method
of thresholding individual biomark-
(b) ers may not be optimal for closed-loop
control. Accurate symptom prediction
FIGURE 2: (a) The concept of adaptive DBS (aDBS) for PD [16]. Bipolar LFP is filtered within often necessitates multiple biomark-
the beta band and smoothed. When the beta power crosses a predefined threshold, stimula-
ers from different input channels,
tion is triggered in a monopolar configuration between the bipolar recording electrodes.
Stimulation ceases when the beta power drops below the threshold. (b) Improvements in increasing system complexity. Fur-
clinical motor score (Unified PD Rating Scale), and the speech intelligibility for various stimu- thermore, recent studies [22], [23],
lation conditions on eight Parkinsonian patients. Modified from [16] and [17]. *Significant [24], [25], [26], [27] highlight the poten-
differences after applying false discovery rate for multiple comparisons correction. cDBS: tial of personalized decoders, particu-
continuous deep-brain stimulation.
larly those utilizing modern machine
learning (ML), for reliable decoding of
brain states in movement disorders
[25], [28], epilepsy [29], [30], [31], [32],
Closed-Loop Implant depression [24], migraine [26], and
Off-Chip memory [22], as well as enhanced
Amplifiers, ADC
Neural Input motor decoding for BCI [23], [33],
Symptom Detection

[34], [35]. However, AI-based closed-

Biomarker Model
Extraction loop control that utilizes external
Training
or cloud-based computing resources
Machine may lead to high telemetry power
Learning and prolonged loop latency, hinder-
ing real-time feedback.
Therapeutic
Stimulation Alternatively, Figure 3 illustrates
Feedback
a conceptual framework for a closed-
loop neural interface empowered by
FIGURE 3: The framework for AI-driven closed-loop stimulation in neural interfaces: On-chip AI. This framework integrates on-chip
biomarker extraction and ML processor facilitate rapid symptom detection and therapeutic biomarker extraction and advanced
feedback, while model training is performed externally. ML algorithms, facilitating real-time

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 decision making within the neural
implant itself, as implemented in a
number of seizure control system-
on-chips (SoCs) in recent years [2],
[29], [30], [31], [32], [36], [37], [38]. Le-
veraging the power of AI in complex
pattern recognition, this framework
holds the potential for broader appli-
cations beyond epilepsy and PD in the
future. It may be utilized to predict
and enhance cognitive p ­ erformance,
detect and improve memory dys-
function, classify and regulate mood
state, decode and facilitate intention-
al movements in paralyzed patients
or amputees, and more.
Table 2 shows the frequently used
biomarkers and ML algorithms em-
ployed for symptom detection and
motor decoding in various brain dis-
orders and BCI applications in the
literature. As illustrated in Table 2,
a wide spectrum of biomarkers with
varying complexity levels exists,
including features extracted in the
time, frequency, and phase domains.
These biomarkers underlie the disease
state in diverse neurological condi-
tions and across patients. This diversi-
ty emphasizes the crucial requirement
for programmable SoC architectures
that can flexibly accommodate the op-
timal feature set specific to an indica-
tion and patient during runtime, while
supporting multiple classification
tasks with high accuracy and minimal
delay. In particular, achieving high ac-
curacy with on-chip AI models, while
simultaneously enabling low-power
operation and prolonged battery life,
In general, closed-loop stimulation offers
the potential for more effective stimulation
compared to its open-loop alternatives,
resulting in reduced side effects and improved
energy efficiency.
is a complex challenge. This requires
a careful selection of the ML model
and extensive co-optimization of al-
gorithms and hardware to meet both
accuracy and energy requirements.
Current closed-loop systems, pri-
marily designed for epilepsy and
PD, have limited channel count and
minimal on-device processing. This
compromises their accuracy and lim-
its their application in more complex
indications that require extensive
measurement of widespread brain
networks using large-scale ECoG
and/or LFP recording. One potential
solution is to enhance the decod-
ing accuracy by increasing the num-
ber and distribution of electrodes, as
promised by technologies, such as
Neuralink. Yet to date, the process-
ing of large-scale neural signals has
predominantly been performed off-
implant [13], [23], [33], [39], necessi-
tating the transmission of massive
data streams via physical or wire-
less links with dedicated power re-
sources. Development of a compact,
energy-efficient, and high-density
AI-driven system has the potential to
significantly impact the closed-loop
neuromodulation and BCI fields.
In the following, we introduce a
cutting-edge closed-loop neural in-
terface SoC [37], [38] that leverages
modern ML and mixed-signal IC de-
sign techniques to achieve exception-
al energy efficiency, channel density,
versatility, and intelligence, setting
new benchmarks in the field.
NeuralTree: Redefining Efficiency,
Versatility, and Scalability in Neural
Interfaces
For closed-loop neuromodulation to
be effective, we need a precise mea-
surement of the source of pathologi-
cal neural activity to enable targeted
stimulation of specific brain regions
for symptom suppression. In the
context of epileptic seizure detec-
tion, for instance, high spatial-res-
olution ECoG recording allows for
precise localization of seizure foci
[40] and improves the performance
of ML-based seizure detectors. In
the management of movement dis-
orders like essential tremor and
PD, increasing the number of DBS
contacts can enhance tremor sup-
pression and minimize side effects
caused by off-target, nonspecific
stimulation. Similarly, high-resolution

TABLE 2. LIST OF RELEVANT BIOMARKERS AND ML MODELS WIDELY USED FOR SYMPTOM DETECTION AND MOVEMENT
DECODING IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS.

MEMORY AND
DISORDERS AND MOVEMENT PSYCHIATRIC
BIOMAKERS EPILEPSY DISORDERS DISORDERS BCI

Biomakers Line length, spectral energy Spectral energy Spectral energy features, Spectral energy
features, phase-locking value, features, Hjorth phase-amplitude features,
phase-amplitude coupling Hjorth parameters, fast and coupling, phase-locking local motor
parameters slow high-frequency value, coherence potential, Hjorth
oscillations (HFO), parameters
HFO ratio, tremor
power, phase-
amplitude coupling
ML Models Support vector machines, XGBoost, LightGBM, random forest, logistic regression, K-nearest neighbors, multilayer
perceptron, convolutional neural network, long short-term memory, spiking neural network

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 SoC
Dense
DBS Lead Cortical Grid 4 mm
2.9 mm
High-Density Disease-Specific

256-Ch. TDM DSL

TDM

Memory
3.17 kB
CS-TDM AFE
Multisite Sensing Biomarkers FEE

1.2 mm
256-Ch.

NeuralTree
16-Ch.

2 mm
Stimulator
Stimulation/ ML Classifier
ion Prosthetic Control (Binary/Multiclass)
ot trol TDM FIR
M n
Co Versatile Closed-Loop Neural Interface Test Blocks and Flip-Chip Pad Array

(a)
Energy-Aware Regularization
Feature Power Feature Distribution
Low Temporal
CH1
CH2 64-Ch 16.6%
Spectral

y
CH3 TDM AFE

e Tr Activit
81.8%
Dual MUX-CHOP

1.6%

ng
High Phase
64-Ch

aini
16 × 16

al
TDM AFE
eura Neur
Switch Matrix
Network Pruning
64-Ch lTre
for N ensity

CH254 TDM AFE f1 fp f2 fp f64

Energy-Aware
CH255
w2 Pruning
h-D

CH256 64-Ch w1 w64

TDM AFE Extracted
Hig

Column Decoder fi
Sigmoid Features
fp Pruned
p = σ (fTw – TH.) Features
(b)

CH1 TDM FEE Single-Path Inference

CH2 LL
CH3
Class Labels

Hjorth
Dual MUX-CHOP

LMP
16 × 16
SE
Y

Switch Matrix 64-Ch HFOR

TDM AFE
CH254 PLV
CH255 PAC
CH256
N

Column Decoder MUX

Memory NeuralTree Hardware (≤ 64 MACs/window)

(2.93 kB) Feature Vector
Y

Channel Index f64 ... f3 f2 f1

Node Addr
Feature Type Weight Vector × + Z –1
Weight w64 ... w3 w2 w1 TH. Decision
Class

Threshold LUT
Dominant Class
(c)

FIGURE 4: NeuralTree: An intelligent, ML-driven closed-loop neural interface [37], [38]. (a) Conceptual system-level diagram, h ­ ighlighting
high-channel-count cortical arrays and depth leads for high-density sensing and stimulation. (b) NeuralTree’s training process involves
256-channel ECoG/LFP sensing, energy-aware regularization, and network pruning. (c) Dynamic inference using an on-chip, versatile,
tree-structured neural network supporting neural signal classification for epilepsy, movement disorders, and BCI. AFE: analog front-end;
FEE: feature extraction engine; HFO: high-frequency oscillation; LL: line length; LMP: local motor potential; LUT: lookup table;
MUX: multiplexer; PAC: phase-amplitude coupling; PLV: phase-locking value; SE: spectral energy; TDM: time-division multiplexing.

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 sensing can significantly improve
the precision of motor decoding in
BCI and enable more natural control
of prosthetic devices. However, the
stringent energy and space limita-
tions in implantable systems pose
significant challenges for integrating
high-accuracy biomarker extraction
and ML, as well as high-density sens-
ing and stimulation on the same chip.
Our AI-enabled closed-loop neural
interface, the NeuralTree [37], [38],
is designed to overcome the limita-
tions of existing systems. It features
a high channel-count (i.e., 256 chan-
nel) sensing array, compatible with
high-density cortical and subcorti-
cal electrodes [Figure 4(a)], enabling
the collection of neural activity from
distributed brain regions associated
with the targeted disease. Addition-
ally, the system provides program-
mable and responsive stimulation
for precise therapeutic intervention.
The direct embedding of a versatile
biomarker extraction and ML model
on the chip enables the detection of
various neurological conditions, ex-
tending beyond epileptic seizures.
The NeuralTree SoC shown in
­Figure 4(a) presents novel circuit
and algorithmic solutions to address
Leveraging the power of AI in complex pattern
recognition, this framework holds the potential
for broader applications beyond epilepsy and
PD in the future.
the limitations of current closed-
loop systems. Importantly, to facili-
tate high-density and scalable neural
activity processing with ultralow
power and minimal area, we have
developed a unique implementation
featuring four 64-channel mixed-
signal front ends with time-division
multiplexing (TDM). These four front
ends enable the processing of 256
channels and incorporate a novel dc
servo loop for two-step, rapid off-
set cancellation [38]. Each front-end
channel occupies only 0.004 mm2 of
area and consumes 1.51 μW of pow-
er. After training the ML model with
high-resolution 256-channel neural
data [Figure 4(b)], 64 channels corre-
sponding to the features of pruned
neural networks are amplified and
directed to the biomarker extrac-
tion and ML modules during infer-
ence, following the active nodes of
a probabilistic decision tree [35]
[Figure 4(c)]. This approach en-
ables high-resolution training and
channel-selective inference, as it is
common for only a subset of chan-
nels to contribute to the underlying
disease state.
By focusing on relevant chan-
nels during inference, we can opti-
mize the system’s performance and
computational efficiency. The Neu-
ralTree classifier also incorporates
an innovative energy-aware regular-
ization approach that discourages
the use of computationally intensive
features [Figure 4(b)], allowing for
an optimal tradeoff between energy
consumption and accuracy during
inference [41].
The flexible SoC can compute a
diverse set of spectral-, time-, and
phase-domain [42], [43] neural bio-
markers tailored to the patient and
disease characteristics, as depicted in
Figure 5. The probabilistic NeuralTree

Temporal Features Epilepsy

Amplitude

LL
Hjorth Parameters (ACT, MOB, COM)
LMP
Time
PLV LL

Spectral Features
Magnitude

SE PAC
SE
HFO Ratio
Frequency
F ACT

HFO
Ratio MOB LMP
Phase Features COM
Phase

PLV
PAC
Time Parkinson’s Finger Movement

FIGURE 5: Multidomain neural biomarkers integrated on the closed-loop NeuralTree SoC [37], [38], supporting various symptom detection
and classification tasks in epilepsy, movement disorders, and BCI. ACT: activity; MOB: mobility; COM: complexity.

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Development of a compact, energy-efficient,
and high-density AI-driven system has the
potential to significantly impact the closed-loop
neuromodulation and BCI fields.
supports both multiclass detection
tasks for BCI applications (e.g., six-
class finger movement and rest) and
binary classification for seizure and
tremor detection, using only 2.93 kB
of on-chip memory. The therapeu-
tic loop is completed by a compact
16-channel high-voltage–compliant
neurostimulator.
The NeuralTree system incorporates
cutting-edge circuit and algorithmic
techniques, such as end-to-end TDM,
feature approximations, and energy-
aware learning, resulting in a new
class of energy and area efficiency.
The chip was successfully verified
using human epilepsy and PD datas-
ets, and in vivo in a rat epilepsy mod-
el, using soft ECoG electrodes [38].
The 256-channel SoC has a small
active area of 3.48 mm2 in a 65-nm
TSMC process and achieves a system
energy efficiency of 0.227 µJ/class,
4.3-times better than state-of-the-
art ML-embedded neural interfaces.
Indeed, the NeuralTree SoC uses sig-
nificantly less power and smaller
footprint per channel compared to the
state-of-the-art closed-loop systems,
while supporting 64-times more
sensing channels than the RNS and
Percept devices. Its modular architec-
ture allows for easy scalability and
customization based on the contri-
butions of different input channels
and signal modalities, and ensures
optimal performance tailored to the
unique characteristics of each dis-
ease and patient.
The NeuralTree system outlined
above offers unique opportunities
for closed-loop AI-controlled disease
management in both established and
emerging neurological indications,
as well as future BCI systems. The
SoC’s remarkably low-power con-
sumption and compact design favors
implantable systems by reducing in-
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vasiveness and prolonging battery
life. Furthermore, the incorporation
of intricate biomarkers and advanced
ML models enhances decoding accu-
racy. Potential avenues for improve-
ment include the incorporation of
low-power front-end circuits capable
of cancelling large stimulation arti-
facts, the integration of dynamics-
aware ML models to accommodate
neural signal fluctuations over time,
and the integration of wireless data
communication (for model training
and chip configuration) and wireless
power transfer circuits with the bidi-
rectional neuromodulation system.
Furthermore, exploring the poten-
tial of brain-inspired neuromorphic
computing models, such as spiking
neural networks (SNNs) for disease
prediction [44], [45] and BCI con-
trol [46] can open new horizons for
even more efficient, low-power, and
adaptable closed-loop interfaces in
the future [47], [48]. The remarkable
energy efficiency of neuromorphic
systems [45] is rooted in their utili-
zation of spike-based computational
paradigms, alongside the intrinsic
error resilience exhibited by SNNs
that can facilitate ultralow-power
subthreshold operation.
Acknowledgment
In-vivo experiments were conducted
in accordance with ethical protocols
and regulations of the Veterinary
Office of the Canton of Geneva,
Switzerland. This work was partially
funded by the Swiss State Secretariat
for Education, Research, and Inno-
vation under Contract SCR0548363.
I thank my students and collabora-
tors at the Swiss Federal Institute of
Technology Lausanne, particularly
Uisub Shin, for their contributions
to the NeuralTree project described
in this article.
MAGAZINE
References
[1] L. Drew, “Decoding the business of brain–
computer interfaces,” Nature Electron.,
vol. 6, no. 2, pp. 90–95, Feb. 2023, doi:
10.1038/s41928-023-00929-9.
[2] B. Zhu, U. Shin, and M. Shoaran, “Closed-
loop neural prostheses with on-chip in-
telligence: A review and a low-latency
machine learning model for brain state de-
tection,” IEEE Trans. Biomed. Circuits Syst.,
vol. 15, no. 5, pp. 877–897, Oct. 2021, doi:
10.1109/TBCAS.2021.3112756.
[3] M. Shaeri, A. Afzal, and M. Shoaran, “Chal-
lenges and opportunities of edge AI for
next-generation implantable BMIs,” in
Proc. IEEE 4th Int. Conf. Artif. Intell. Cir-
cuits Syst. (AICAS), Jun. 2022, pp. 190–193,
doi: 10.1109/AICAS54282.2022.9870008.
[4] J. K. Krauss et al., “Technology of deep
brain stimulation: Current status and fu-
ture directions,” Nature Rev. Neurol., vol.
17, no. 2, pp. 75–87, Feb. 2021, doi: 10.1038/
s41582-020-00426-z.
[5] F. T. Sun and M. J. Morrell, “The RNS sys-
tem: Responsive cortical stimulation
for the treatment of refractory partial
epilepsy,” Expert Rev. Med. Devices, vol.
11, no. 6, pp. 563–572, Nov. 2014, doi:
10.1586/17434440.2014.947274.
[6] N. Naseer and K.-S. Hong, “fNIRS-based
brain-computer interfaces: A review,”
Frontiers Hum. Neurosci., vol. 9, Jan. 2015,
Art. no. 3. Accessed: Jul. 15, 2023. [On-
line]. Available: https://www.frontiersin.
org/articles/10.3389/fnhum.2015.00003.
[7] P. Bowary and B. D. Greenberg, “Noninva-
sive focused ultrasound for neuromodu-
lation: A review,” Psychiatric Clinics, vol.
41, no. 3, pp. 505–514, Sep. 2018, doi:
10.1016/j.psc.2018.04.010.
[8] M. Hallett, “Transcranial magnetic stimu-
lation: A primer,” Neuron, vol. 55, no. 2,
pp. 187–199, Jul. 2007, doi: 10.1016/j.neu-
ron.2007.06.026.
[9] N. Grossman et al., “Noninvasive deep
brain stimulation via temporally interfer-
ing electric fields,” Cell, vol. 169, no. 6,
pp. 1029–1041, Jun. 2017, doi: 10.1016/
j.cell.2017.05.024.
[10] W. Bouthour, P. Mégevand, J. Donoghue, C.
Lüscher, N. Birbaumer, and P. Krack, “Bio-
markers for closed-loop deep brain stimula-
tion in Parkinson disease and beyond,” Na-
ture Rev. Neurol., vol. 15, no. 6, pp. 343–352,
Jun. 2019, doi: 10.1038/s41582-019-0166-4.
[11] M. Zamora et al., “DyNeuMo Mk-1: Design
and pilot validation of an investigational
motion-adaptive neurostimulator with
integrated chronotherapy,” Exp. Neurol.,
vol. 351, May 2022, Art. no. 113977, doi:
10.1016/j.expneurol.2022.113977.
[12] N. A. Steinmetz et al., “Neuropixels 2.0: A
miniaturized high-density probe for sta-
ble, long-term brain recordings,” Science,
vol. 372, no. 6539, Apr. 2021, Art. no.
eabf4588, doi: 10.1126/science.abf4588.
[13] D.-Y. Yoon, S. Pinto, S. Chung, P. Merolla,
T.-W. Koh, and D. Seo, “A 1024-channel
simultaneous recording neural SoC with
stimulation and real-time spike detec-
tion,” in Proc. Symp. VLSI Circuits, Jun.
2021, pp. 1–2, doi: 10.23919/VLSICircuits52068.
2021.9492480.
[14] K. Sahasrabuddhe et al., “The Argo: A high
channel count recording system for neu-
ral recording in vivo,” J. Neural Eng., vol.
18, no. 1, Feb. 2021, Art. no. 015002, doi:
10.1088/1741-2552/abd0ce.
[15] A. M. Lozano et al., “Deep brain stimula-
tion: Current challenges and future direc-
tions,” Nature Rev. Neurol., vol. 15, no.
3, pp. 148–160, Mar. 2019, doi: 10.1038/
s41582-018-0128-2.
 [16] S. Little et al., “Adaptive deep brain stim-
ulation in advanced Parkinson disease,”
Ann. Neurol., vol. 74, no. 3, pp. 449–457,
Sep. 2013, doi: 10.1002/ana.23951.
[17] S. Little et al., “Adaptive deep brain stimula-
tion for Parkinson’s disease demonstrates
reduced speech side effects compared to
conventional stimulation in the acute set-
ting,” J. Neurol. Neurosurg. Psychiatry, vol.
87, no. 12, pp. 1388–1389, Dec. 2016, doi:
10.1136/jnnp-2016-313518.
[18] M. Shoaran et al., “A 16-channel 1.1 mm2
implantable seizure control SoC with
sub-μW/channel consumption and closed-
loop stimulation in 0.18 µm CMOS,” in Proc.
IEEE Symp. VLSI Circuits (VLSI-Circuits),
Jun. 2016, pp. 1–2, doi: 10.1109/VLSIC.
2016.7573557.
[19] M. Shoaran, C. Pollo, K. Schindler, and A.
Schmid, “A fully integrated IC with 0.85-μW/
channel consumption for epileptic iEEG
detection,” IEEE Trans. Circuits Syst., II,
Exp. Briefs, vol. 62, no. 2, pp. 114–118, Feb.
2015, doi: 10.1109/TCSII.2014.2387652.
[20] M. S. Okun et al., “A trial of scheduled
deep brain stimulation for Tourette syn-
drome: Moving away from continuous
deep brain stimulation paradigms,” JAMA
Neurol., vol. 70, no. 1, pp. 85–94, Jan.
2013, doi: 10.1001/jamaneurol.2013.580.
[21] K. W. Scangos et al., “Closed-loop neuro-
modulation in an individual with treat-
ment-resistant depression,” Nature Med.,
vol. 27, no. 10, pp. 1696–1700, Oct. 2021,
doi: 10.1038/s41591-021-01480-w.
[22] Y. Ezzyat et al., “Closed-loop stimulation
of temporal cortex rescues functional
networks and improves memory,” Nature
Commun., vol. 9, no. 1, Feb. 2018, Art. no.
365, doi: 10.1038/s41467-017-02753-0.
[23] H. Lorach et al., “Walking naturally after
spinal cord injury using a brain–spine
interface,” Nature, vol. 618, no. 7963, pp.
126–133, Jun. 2023, doi: 10.1038/s41586-
023-06094-5.
[24] O. G. Sani, Y. Yang, M. B. Lee, H. E. Dawes, E. F.
Chang, and M. M. Shanechi, “Mood variations
decoded from multi-site intracranial hu-
man brain activity,” Nature Biotechnol.,
vol. 36, no. 10, pp. 954–961, Nov. 2018,
doi: 10.1038/nbt.4200.
[25] L. Yao, P. Brown, and M. Shoaran, “Im-
proved detection of Parkinsonian resting
tremor with feature engineering and Kal-
man filtering,” Clin. Neurophysiol., vol.
131, no. 1, pp. 274–284, Jan. 2020, doi:
10.1016/j.clinph.2019.09.021.
[26] B. Zhu, G. Coppola, and M. Shoaran, “Mi-
graine classification using somatosen-
sory evoked potentials,” Cephalalgia, vol.
39, no. 9, pp. 1143–1155, Aug. 2019, doi:
10.1177/0333102419839975.
[27] L. Yao, J. L. Baker, N. D. Schiff, K. P. Pur-
pura, and M. Shoaran, “Predicting task
performance from biomarkers of mental
fatigue in global brain activity,” J. Neural
Eng., vol. 18, no. 3, Mar. 2021, Art. no.
036001, doi: 10.1088/1741-2552/abc529.
[28] L. Yao, P. Brown, and M. Shoaran, “Resting
tremor detection in Parkinson’s disease
with machine learning and Kalman filter-
ing,” in Proc. IEEE Biomed. Circuits Syst.
Conf. (BioCAS), Oct. 2018, pp. 1–4, doi:
10.1109/BIOCAS.2018.8584721.
Authorized licensed use limited to: EPFL LAUSANNE. Downloaded on November 18,2023 at 16:44:53 UTC from CIRCUITS MAGAZINE
View publication stats
[29] J. Yoo, L. Yan, D. El-Damak, M. A. B. Al-
taf, A. H. Shoeb, and A. P. Chandrakasan,
“An 8-channel scalable EEG acquisition
SoC with patient-specific seizure clas-
sification and recording processor,”
IEEE J. Solid-State Circuits, vol. 48, no. 1,
pp. 214–228, Jan. 2013, doi: 10.1109/JSSC.
2012.2221220.
[30] M. Shoaran, B. A. Haghi, M. Taghavi, M.
Farivar, and A. Emami-Neyestanak, “En-
ergy-efficient classification for resource-
constrained biomedical applications,”
IEEE J. Emerg. Sel. Topics Circuits Syst.,
vol. 8, no. 4, pp. 693–707, Dec. 2018, doi:
10.1109/JETCAS.2018.2844733.
[31] G. O’Leary, D. M. Groppe, T. A. Valiante,
N. Verma, and R. Genov, “NURIP: Neural
interface processor for brain-state clas-
sification and programmable-waveform
neurostimulation,” IEEE J. Solid-State Cir-
cuits, vol. 53, no. 11, pp. 3150–3162, Nov.
2018, doi: 10.1109/JSSC.2018.2869579.
[32] A. Chua, M. I. Jordan, and R. Muller,
“SOUL: An energy-efficient unsupervised
online learning seizure detection classifi-
er,” IEEE J. Solid-State Circuits, vol. 57, no.
8, pp. 2532–2544, Aug. 2022, doi: 10.1109/
JSSC.2022.3172231.
[33] F. R. Willett, D. T. Avansino, L. R. Hoch-
berg, J. M. Henderson, and K. V. Shenoy,
“High-performance brain-to-text commu-
nication via handwriting,” Nature, vol.
593, no. 7858, pp. 249–254, May 2021, doi:
10.1038/s41586-021-03506-2.
[34] L. Yao, B. Zhu, and M. Shoaran, “Fast and
accurate decoding of finger movements
from ECoG through Riemannian features
and modern machine learning tech-
niques,” J Neural Eng., vol. 19, no. 1, Feb.
2022, Art. no. 016037, doi: 10.1088/1741-
2552/ac4ed1.
[35] B. Zhu, M. Farivar, and M. Shoaran, “ResOT:
Resource-efficient oblique trees for neu-
ral signal classification,” IEEE Trans.
Biomed. Circuits Syst., vol. 14, no. 4, pp. 692–
704, Aug. 2020, doi: 10.1109/TBCAS.2020.
3004544.
[36] M. A. Bin Altaf and J. Yoo, “A 1.83 μJ/clas-
sification, 8-channel, patient-specific epi-
leptic seizure classification SoC using a
non-linear support vector machine,” IEEE
Trans. Biomed. Circuits Syst., vol. 10, no. 1,
pp. 49–60, Feb. 2016, doi: 10.1109/TBCAS.
2014.2386891.
[37] U. Shin et al., “A 256-channel 0.227 µJ/class
versatile brain activity classification and
closed-loop neuromodulation SoC with
0.004 mm2-1.51 µW/channel fast-settling
highly multiplexed mixed-signal front-
end,” in Proc. IEEE Int. Solid-State Circuits
Conf. (ISSCC), Feb. 2022, pp. 338–340, doi:
10.1109/ISSCC42614.2022.9731776.
[38] U. Shin et al., “NeuralTree: A 256-channel
0.227-μJ/class versatile neural activity
classification and closed-loop neuromod-
ulation SoC,” IEEE J. Solid-State Circuits,
vol. 57, no. 11, pp. 3243–3257, Nov. 2022,
doi: 10.1109/JSSC.2022.3204508.
[39] J. D. Simeral et al., “Home use of a per-
cutaneous wireless intracortical brain-
computer interface by individuals with
tetraplegia,” IEEE Trans. Biomed. Eng., vol.
68, no. 7, pp. 2313–2325, Jul. 2021, doi:
10.1109/TBME.2021.3069119.
IEEE SOLID-STATE
IEEE Xplore. Restrictions FA LL 2023
[40] M. Shoaran, M. H. Kamal, C. Pollo, P. Van-
dergheynst, and A. Schmid, “Compact
low-power cortical recording architec-
ture for compressive multichannel data
­acquisition,” IEEE Trans. Biomed. Circuits
Syst., vol. 8, no. 6, pp. 857–870, Dec. 2014,
doi: 10.1109/TBCAS.2014.2304582.
[41] B. Zhu, M. Taghavi, and M. Shoaran, “Cost-
efficient classification for neurological
disease detection,” in Proc. IEEE Biomed.
Circuits Syst. Conf. (BioCAS), Oct. 2019, pp.
1–4, doi: 10.1109/BIOCAS.2019.8918702.
[42] U. Shin, C. Ding, V. Woods, A. S. Widge,
and M. Shoaran, “A 16-channel low-power
neural connectivity extraction and phase-
locked deep brain stimulation SoC,” IEEE
Solid-State Circuits Lett., vol. 6, pp. 21–24,
Jan. 2023, doi: 10.1109/LSSC.2023.3238797.
[43] U. Shin, C. Ding, L. Somappa, V. Woods,
A. S. Widge, and M. Shoaran, “A 16-channel
60 µW neural synchrony processor for
multi-mode phase-locked neurostimu-
lation,” in Proc. IEEE Custom Integr. Cir-
cuits Conf. (CICC), Apr. 2022, pp. 1–2, doi:
10.1109/CICC53496.2022.9772806.
[44] M. Sharifshazileh, K. Burelo, J. Sarnthein,
and G. Indiveri, “An electronic ­neuromorphic
system for real-time detection of high fre-
quency oscillations (HFO) in intracranial
EEG,” Nature Commun., vol. 12, no. 1, May
2021, Art. no. 3095, doi: 10.1038/s41467-021-
23342-2.
[45] M. Ronchini, Y. Rezaeiyan, M. Zamani,
G. Panuccio, and F. Moradi, “NET-TEN: A
silicon neuromorphic network for low-­
latency detection of seizures in local field
potentials,” J. Neural Eng., vol. 20, no. 3,
Jun. 2023, Art. no. 036002, doi: 10.1088/
1741-2552/acd029.
[46] H. Fares, M. Ronchini, M. Zamani, H.
Farkhani, and F. Moradi, “In the realm of
hybrid Brain: Human brain and AI,” Oct.
2022, arXiv:2210.01461.
[47] C. Fang, C. Wang, S. Zhao, F. Tian, J. Yang,
and M. Sawan, “A 510 μW 0.738-mm 2
6.2-pJ/SOP online learning multi-topolo-
gy SNN processor with unified computa-
tion engine in 40-nm CMOS,” IEEE Trans.
Biomed. Circuits Syst., vol. 17, no. 3, pp.
507–520, Jun. 2023, doi: 10.1109/TBCAS.
2023.3279367.
[48] J. Yoo and M. Shoaran, “Neural interface
systems with on-device computing: Ma-
chine learning and neuromorphic archi-
tectures,” Current Opinion Biotechnol., vol.
72, pp. 95–101, Dec. 2021, doi: 10.1016/
j.copbio.2021.10.012.
About the Author
Mahsa Shoaran (mahsa.shoaran@
epfl.ch) is an assistant professor in
electrical engineering and Neuro-X
and director of the Integrated Neuro-
technologies Laboratory at the Swiss
Federal Institute of Technology Lau-
sanne, 1015 Lausanne, Switzerland.
She is a Senior Member of IEEE.

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