Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics in Neuronal Cells

Abstract

In neurons and myocytes, selective ion channels in the plasma membrane play a pivotal role in transducing chemical or sensory stimuli into electrical signals, underpinning neural and cardiac functionality. Recent advancements in biomedical research have increasingly spotlighted the interaction between ion channels and electromagnetic fields, especially terahertz (THz) radiation. This review synthesizes current findings on the impact of THz radiation, known for its deep penetration and non-ionizing properties, on ion channel kinetics and membrane fluid dynamics. It is organized into three parts: the biophysical effects of THz exposure on cells, the specific modulation of ion channels by THz radiation, and the potential pathophysiological consequences of THz exposure. Understanding the biophysical mechanisms underlying these effects could lead to new therapeutic strategies for diseases.

Full text

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Neurosci. Bull.
https://doi.org/10.1007/s12264-024-01277-0
REVIEW
www.neurosci.cn
www.springer.com/12264
Progress oftheImpact ofTerahertz Radiation onIon Channel
Kinetics inNeuronal Cells
YanjiangLiu1· XiLiu1,2,3,4,5,6· YoushengShu1,2,4,5·
YuguoYu1,2,3,7
Received: 26 December 2023 / Accepted: 12 April 2024
© Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences 2024
Abstract In neurons and myocytes, selective ion channels
in the plasma membrane play a pivotal role in transducing
chemical or sensory stimuli into electrical signals, under-
pinning neural and cardiac functionality. Recent advance-
ments in biomedical research have increasingly spotlighted
the interaction between ion channels and electromagnetic
fields, especially terahertz (THz) radiation. This review syn-
thesizes current findings on the impact of THz radiation,
known for its deep penetration and non-ionizing proper-
ties, on ion channel kinetics and membrane fluid dynamics.
It is organized into three parts: the biophysical effects of
THz exposure on cells, the specific modulation of ion chan-
nels by THz radiation, and the potential pathophysiological
consequences of THz exposure. Understanding the biophysi-
cal mechanisms underlying these effects could lead to new
therapeutic strategies for diseases.
Keywords Ion channel kinetics· Terahertz radiation·
Electromagnetic field interactions· Neuron· Cell
membrane
Introduction
Neurons, as the quintessential units of the nervous system,
exhibit unique sensitivity and excitability crucial for cellular
communication [1]. The material basis for the vital neural
function lies in the essential proteins embedded in the cell
membrane, namely ion channels. These ion channels possess
a central aqueous pore, through which ions swiftly move
in and out, thereby initiating and propagating action poten-
tials. Neurons typically fire action potentials at frequencies
between 0.1 and 200Hz [2].
Recent advances have underscored the intriguing sensi-
tivity of these ion channels to electromagnetic fields [3],
particularly within the terahertz (THz) spectrum [4–6] rang-
ing from 0.1 to 100THz [2]. The THz wave has attracted
substantial interest due to its non-ionizing nature and deep
penetration capabilities. Terahertz waves span a diverse
array of applications, from cosmic microwave background
and stellar emissions to transitions in atoms and semicon-
ductors. They exert significant biological effects at several
levels, from macromolecules to whole organisms, potentially
causing unique phenotypic alterations in both animals and
humans. Despite its significant potential in biomedical appli-
cations, studies on terahertz waves have faced challenges of
radiation source and detection, leading to a delayed com-
mencement of systematic study. The term "terahertz" was
Yanjiang Liu and Xi Liu contributed equally to this review.
* Yousheng Shu
yousheng@fudan.edu.cn
* Yuguo Yu
yuyuguo@fudan.edu.cn
1 Research Institute ofIntelligent andComplex Systems,
Fudan University, Shanghai200433, China
2 MOE Frontiers Center forBrain Science andState Key
Laboratory ofMedical Neurobiology, Fudan University,
Shanghai200433, China
3 Institute ofScience andTechnology forBrain-Inspired
Intelligence, Fudan University, Shanghai200433, China
4 Department ofNeurology, Huashan Hospital, Fudan
University, Shanghai20043, China
5 Institute forTranslational Brain Research, Fudan University,
Shanghai200433, China
6 Department ofNeurosurgery, Jinshan Hospital ofFudan
University, Shanghai201508, China
7 Shanghai Artificial Intelligence Laboratory,
Shanghai200232, China

Neurosci. Bull.
coined in the 1970s, although its origins can be traced back
over a century. Notably, biomedical applications of terahertz
technology began to gain traction in the 1980s. The early
21st century experienced a global surge in terahertz research
efforts, particularly after its 2004 identification as a trans-
formative technology by the U.S. government [7, 8].
The allure of terahertz radiation lies in its distinctive
nature, including non-ionizing property that ensures the
absence of radical-mediated tissue damage [9], exemplary
penetration through non-conductive materials while facing
limitations in traversing metals [10], atmospheric attenu-
ation caused by water vapor absorption [11], differential
absorption rates in biological tissues owing to their water
content [12], resonance with vibrational transitions of
numerous biomolecules [13], and its unique position at the
photonics-electronics cusp [14]. Moreover, the bandwidth
supremacy of terahertz waves over microwaves holds impli-
cations for next-generation communications [5, 15, 16] and
diverse applications spanning physics to medical diagnostics
[17–21].
At the molecular level, ion channels emerge as suscep-
tible biomolecules to terahertz radiations. As a facet of
electromagnetic radiation, terahertz waves modulate ionic
movements via resonant frequencies. Contemporary research
suggests an array of perturbations of ion channel activity by
terahertz wave, including heightened channel permeabilities,
potential generation during ionic transport, and the putative
roles of these waves in organismal health.
Emerging insights necessitate delving into pivotal
research trajectories: (1) exploring the underlying rationale
for the terahertz wave-mediated modulation of organisms
and cell membranes; (2) establishing plausible interaction
mechanisms between terahertz waves and ion channels; (3)
exploring potential biomedical applications of terahertz
waves. This manuscript endeavors to synthesize contempo-
rary insights spanning the three trajectories.
Thermal andNon‑thermal Effects ofTerahertz
Waves onBiological Organisms
The electromagnetic spectrum encompasses a diverse range
of wavelengths, each with distinct physical properties and
interactions [22]. Radio waves, situated at one end of this
spectrum, are inherently associated with the field of elec-
tronics due to their longer wavelengths and lower frequen-
cies [23]. Conversely, light waves, found at the opposite
end, correlate with photonics, characterized by their shorter
wavelengths and higher frequencies [22]. Bridging these two
domains is the terahertz (THz) frequency band, occupying
a unique transitional region that amalgamates the charac-
teristics of both microwave and infrared wavelengths [14].
This intermediary position makes the THz band particularly
elusive, as it does not fully conform to the principles gov-
erning either optical or microwave electronic theories [24].
What distinguishes the THz band within the electromag-
netic spectrum is its capacity to elicit distinctive biologi-
cal responses [2, 9, 25]. Despite the macroscopic electrical
neutrality prevalent in biological organisms, the microscopic
behavior of charged ions, polar molecules, and electric fields
adheres to the principles of electromagnetism and thermo-
dynamics. This micro-level behavior forms the basis for the
sensitivity of biological systems to electromagnetic influ-
ences, with the THz range being no exception [26]. The
biological effects of THz radiation can be broadly catego-
rized into two types: thermal [27] and non-thermal effects
[9]. Thermal effects have primarily resulted from the energy
absorption by biomolecules, leading to an increase in tem-
perature, which can induce changes in molecular dynamics
and biochemical reactions [27, 28]. In contrast, non-thermal
effects, occurring without a significant temperature rise,
involve alterations in cellular and molecular structures and
functions, potentially impacting biological processes such as
cell signaling and gene expression [17, 29, 30].
The exploration of these effects not only enhances our
understanding of biophysical interactions within the THz
spectrum but also unveils opportunities for novel appli-
cations in medical diagnostics and treatment. The unique
properties of THz waves can be harnessed for therapeu-
tic benefits, showcasing the potential for transformative
advancements in healthcare [9, 18, 25, 31, 32].
Thermal Influences ofTerahertz Waves
THz waves have profound effects on biological systems, pri-
marily through two mechanisms: the absorption by water
molecules and resonance with biological macromolecules.
Organisms such as the human body that have 50%–70%
water content [33, 34] can absorb THz waves effectively.
The frequencies of THz waves [35] are in harmony with
the vibrational frequencies of water’s hydrogen bonds, lead-
ing to significant absorption by biological tissues [36, 37].
This interaction is crucial as it generates thermal energy and
alters cellular functions.
Furthermore, THz waves interact with key biological
macromolecules, such as DNA and proteins, influencing
their activity via vibrational modes [38, 39]. This reso-
nant interaction not only generates thermal energy but also
results in distinct spectral signatures [40], highlighting the
specific absorption peaks of nucleic acid bases within the
THz band, as demonstrated by studies like those of Yu et
al. [41] and Fischer et al. [42]. This evidence supports the
theory that biological tissues have a natural affinity for THz
wave absorption, largely because these waves can induce
linear resonance in biological macromolecules, leading to
heat generation [43–47].

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
Besides direct interactions with water molecules, THz
waves also affect other biological molecules, including cal-
cium channels in excitable cells such as neurons and cardio-
myocytes [48–51]. These channels, crucial for modulating
calcium ion concentrations, are activated by THz radia-
tion, causing membrane potential vibrations and leading
to increased Ca2+ influx, thereby raising intracellular Ca2+
levels. Computational models have further shown that THz
Gaussian pulses, compared to sine waves, can modulate cal-
cium currents with reduced temperature increases [52], sug-
gesting a nuanced approach to understanding and potentially
leveraging THz wave interactions in biological systems.
This concise overview integrates the fundamental inter-
actions of THz waves with biological systems, highlighting
their potential to induce both thermal and resonant effects.
Such insights are pivotal for advancing our understanding of
THz wave applications in neuroscience and medical diagnos-
tics, offering a gateway to novel therapeutic and diagnostic
tools.
Non‑thermal Effect ofTerahertz Radiation
onBiological Systems
Terahertz (THz) radiation uniquely influences biological sys-
tems through non-thermal effects, aligning with the vibra-
tional frequencies of biological macromolecules and human
cellular structures [53]. Unlike thermal impacts, these effects
induce molecular and cellular alterations without tempera-
ture increase, highlighting non-thermal mechanisms as key
in THz interactions with biological entities [54].
The THz spectrum overlaps with the energy states of
proteins, DNAs, and RNAs (1.2–83.0meV) and their
vibrational states (25.0–1000.0meV), suggesting potential
structural and functional changes in these molecules under
THz exposure [38]. Proteins, sensitive to THz due to their
intricate structures and non-covalent bonding, undergo
changes in molecular dynamics, affecting their structure
and function [55, 56]. THz radiation also impacts cellular
functions, including genetic stability, membrane permeabil-
ity, metabolism, and neuronal excitability [4, 57]. Despite
being non-ionizing, intense THz radiation’s electric field
strengths pose potential cell health risks [47]. Studies detail
THz-induced molecular perturbations, highlighting acceler-
ated DNA denaturation and actin polymerization processes
[58–60]. These effects suggest THz radiation can influence
actin filament nucleation and elongation, crucial for cellular
structure [60].
In summary, THz radiation’s non-thermal effects on bio-
logical systems span molecular to cellular levels, distinct
from other electromagnetic frequencies. This underlines the
complexity of THz-biological interactions and the impor-
tance of further research into their health implications.
The Effect ofTerahertz Waves onIon Channels
Structure andFunction ofIon Channels
Ion channels [61] are composed of various channel pro-
teins embedded within the phospholipid bilayer, crucial
for the diffusion-mediated translocation of ions and other
entities. The activity of ion channels participates in many
biological processes including cellular metabolic processes,
homeostatic balance, cell-to-extracellular exchanges [62],
and transmembrane potential generation. Ion channels,
depending on the transported ion types, utilize diverse trans-
membrane mechanisms crucial for the selective passage of
charged inorganic ions via specific functional proteins. This
process is essential for cellular functions requiring ion trans-
port [61, 62].
Resembling electronic transistors, ion channels on neu-
ronal membranes act as natural nanoscale regulators of
electrical activities in neurons. They are instrumental in
maintaining neuronal structural integrity and orchestrating
various neuronal functions [62]. The flow of ions through
these voltage-gated channels generates a current that
modulates membrane voltage (Fig.1), with the kinetics of
these channels supporting the rapid transmission of nerve
impulses [63–65]. Furthermore, these channels are pivotal
in diverse cellular functionalities, including muscle contrac-
tions and organ secretions [66].
Ion channels can transition between two states—open
(activated), or closed (resting or inactivated)—as illustrated
in Fig.1A The activated state facilitates the passive transport
of ions, governed by potential differences or ionic concen-
tration gradients, to equilibrate ion levels inside and out-
side the cell. Ion channels are categorized into three types,
each modulated by distinct triggers: ligand binding, changes
in membrane voltage, and mechanical forces [61, 67], as
depicted in Fig.1B. In addition to gated ion channels, there
is a type called non-gated or ’leak’ channels, which remain
perpetually open, allowing ions to continuously pass through
at a consistent rate. Gated ion channels, in contrast, exhibit
rapid kinetics that enable swift activation and deactivation,
crucial for the propagation of nerve impulses within nar-
rowly defined timeframes.
Voltage-gated ion channels, predominantly in a resting
state, play a significant role in action potential generation
and propagation, while ligand-gated channels, responsive
to specific neurotransmitters, are crucial for interneuronal
communication [62, 68]. Depending on the specific entities
being transported, diverse transmembrane transport modali-
ties come into play [69]. Since essential inorganic ions for
cells are charged and cannot traverse the hydrophobic phos-
pholipid bilayer directly, they necessitate passage via spe-
cific functional proteins, such as ion channels, to effectuate
transmembrane transport [62, 68].

Neurosci. Bull.
Considering the fundamental role of ion channels in neu-
ronal and cellular functions, it’s crucial to understand how
external factors, like terahertz radiation, might influence
their operation [6, 53, 70, 71]. Terahertz radiation, with its
unique frequency properties, has the potential to alter the
behavior and functionality of these ion channels, a topic of
growing interest in neuroscience research [72]. The follow-
ing discussion will delve into the specific effects of terahertz
radiation on ion channels, exploring both its direct impacts
and broader implications for neuronal activity and health.
Recent Progress ofTerahertz Influence onIon
Channels
In contemporary cellular membrane studies, the response of
ion channels to terahertz radiation has emerged as a pivotal
research domain. Terahertz radiation can modify the intra-
cellular electric field distribution, consequently influencing
the status of voltage-gated ion channels [51, 73]. Such modi-
fications can govern ion transportation across the membrane,
leading to alterations in intra- and extracellular ion concen-
trations. Furthermore, terahertz radiation has the capability
to induce the formation of hydrophilic transmembrane pores,
enabling the transit of certain hydrophilic macromolecules
that ordinarily cannot permeate the membrane directly [74].
This implies that terahertz radiation can modulate ion chan-
nel permeability and the transmembrane ion flux [6, 51, 73].
Bo et al. developed a comprehensive mathematical para-
digm to elucidate transmembrane transport phenomena
specific to calcium ions. Their meticulous analysis revealed
that electrical impulses on the nanosecond scale can indeed
activate a subset of voltage-gated calcium channels [75].
Analogously, terahertz radiation affects not just the ions but
the structural and functional dynamics of the ion channel
itself [76, 77].
Traditional neuron models, like the renowned Hodgkin-
Huxley model, produce neural signals within the kilohertz
frequency spectrum. These signals, due to their constrained
bandwidth, are prone to mutual interference. Addressing these
inherent limitations, Liu’s group pioneered an innovative pre-
dictive framework rooted in quantum optics and electrodynam-
ics. Their insights into the electromagnetic fields engendered
by orderly-arranged water molecules on neuron membranes led
them to postulate that the electromagnetic radiation on neuron
surfaces resides within the generalized terahertz range. They
posited the congruence of electromagnetic signal processes
Fig. 1 A An ionic channel on the cell membrane, highlighting its
placement and alignment in the lipid bilayer. Taking a ligand-gated
channel as an example, this panel demonstrates a closed (inactivated)
state and an open (activated) state, which block and permit ion flux
through the channel pore, respectively. B Other example types of ion
channels are permanently open, voltage-gated, and mechanically-
gated channels. The open and closed states are shown for comparison.

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
in neurons with electromagnetic fields and quantum theory,
suggesting that terahertz waves resonate with the eigenmodes
of the nervous system, invoking an array of intricate physical
responses [4, 78–82].
Grounded in preceding scholarship, neural signals journey-
ing along axons are invariably modulated by water molecules.
The structured, orderly arrangement of these molecules can
substantially attenuate signal absorption within the terahertz
spectrum. Furthermore, conditions exist for the spontaneous
structured assembly of these water molecules proximate to
neuron surfaces, as depicted in Fig.2A [4].
For elucidating the neural signal transmission dynamics,
Liu’s group derived the Lagrangian for the entire system, as
presented in Eq. (1), rooted in prior investigations [4],
and
where
b+
ln
and

bln
is the production and annihilation operator
of the
lth
water molecule, respectively.
Assuming electrolytic solutions as continuums and posit-
ing that water molecules adopt an ordered configuration, the
analytical model provides the system’s dynamic equation, as
seen in Eq. (3) based on a previous study [4],
(1)
L=L
H
2
O
+L
field
+L
ion
+L
field
−
H
2
O
.
(2)
L
H2O=
i
2
∑
l,n
(
b+
ln

bln −
b+
lnbln
)
−
∑
l,n
𝜀nb+
lnbln
.
where
𝜆
equals 1 or 2 is the subscript of the transverse field,
𝜆
equals 3 is the subscript of the longitudinal field,
|
|
𝜓
m
|
|
2
is
the number of water molecules in the energy level
m
in unit
volume (
m=1, 2
).
In conditions of minimal or no perturbations, the system
exhibits stability, facilitating the application of perturbation
techniques to decipher the equation, yielding stable solutions
represented in Eq. (4) based on previous study [4],
where
B2
0
+B
2
1
=
n
,
n
means the number of water molecules
in energy level 0 and 1 in unit volume.
The eigen-equation for the electromagnetic field is thus
obtainable as Eq. (5) [4].
where
𝜔2
p
=
∑
l
⟨
nl
⟩
q
2
l
∕𝜀m
l
is the plasma oscillation fre-
quency,
c
is the speed of light, and
𝛽
is the ion sound velocity.
And when
𝜆
is 1 or 2,
c𝜆=c
, when
𝜆
is 3,
c𝜆=𝛽
.
(3)





i𝜓 0=𝜀0𝜓0−

𝜆𝜂𝜆A𝜆𝜓1,
i𝜓 1=𝜀1𝜓1−𝜆𝜂𝜆A𝜆𝜓0,

A𝜆+𝜔2
pA𝜆−c2
𝜆∇2A𝜆=𝜂𝜆𝜓+
0𝜓1+𝜓0𝜓+
1
.
(4)
𝜓0=B0eiΩt
,𝜓
1=B1eiΩt
,
A𝜆=const.
(5)
𝜔
2ΔA𝜆−

𝜔2
p+c2
𝜆k2

ΔA𝜆+
2𝜔
2
0𝜔
2
p
g

g2𝜔2
0
−𝜔2

𝛿𝜆

𝛽
𝛿𝛽ΔA𝛽=
0.
Fig. 2 A Water molecules and
their ordered structures near
the axon surface of neurons. B
Schematic of dispersion curve
ω-k, reflecting the general trend
of dispersion curves of different
modes; when the initial field is
weak (C) and the field is strong
(D). Figures are modified from
reference [4].

Neurosci. Bull.
The solutions derived manifest as four distinct eigen-
modes, with their associated dispersion curves illustrated
in Fig.2B. During instances of substantial interference, the
perturbative approach becomes inapplicable. Consequently,
Eq. (2) undergoes numerical resolution, and the waveforms
under conditions of both weak and robust initial fields are
reassessed, as portrayed in Fig.2C, D [4]. A comparative
analysis of these numerical outputs under varying condi-
tions reveals the excitation of some nonlinear modes during
high initial field strengths, leading to observed disparities
between numerical and analytical outcomes.
Ions inherently migrate towards regions of diminished
potential energy, necessitating surmounting a potential
energy barrier when transitioning in the antithetical direc-
tion. Consequently, the distribution of free energy elucidates
the challenges encountered by ion transversing channels
[83]. Research simulations conducted by Li et al. [51], uti-
lizing CHARMM-GUI, discerned that terahertz radiation
augments the translocation of calcium ions through calcium
channels.
By employing terahertz radiation across varied frequen-
cies, characterized by a field strength of 0.6 V/m, Li et al.
[51] discerned that at a frequency of 42.55 THz, the apex of
the PMF (Potential of Mean Force) curve associated with
the calcium channel was notably diminished. This reduction
signified a consequential decrease in the free energy at the
majority of binding locales within the channel, as delineated
in Fig.3A Their analysis underscored a pivotal alteration
in the carboxyl (−COO−) group of the calcium channel’s
selectivity filter binding site at this frequency. This modifica-
tion enhanced its selectivity towards calcium ions. Given the
expansive influence of the carboxyl group on calcium ions,
this not only expedited their ingress into the selectivity filter
but also hastened their egress, markedly ameliorating the
permeability of calcium ions, as referenced in citation [51].
Using analyzation of the carboxyl and carbonyl groups
in SF after MD simulation, the absorption spectrum was
calculated, as shown in Fig.3B, which illustrated that the
asymmetric stretching mode of the carboxyl group retains
strong water absorption. Through molecular dynamics simu-
lation, the team procured the vibrational spectrum of the
carbon-oxygen bond within the carboxyl group, as depicted
in Fig.3C–F. It was observed that resonance at 42.55 THz
augmented the oscillation amplitude of the carbon-oxygen
bond, yielding markedly elevated spectral intensities. Con-
versely, the non-resonance domain of 51.61 THz was potent
Fig. 3 A The free energy
distribution of Ca2+ ions under
different radiation conditions;
the curves are approximated by
the curves of mean force poten-
tial; B the spectrum of the bulk
water (green) and the spectrum
of the carboxyl and carbonyl
groups (orange); oscillation
spectra of C=O bond lengths in
−COO− groups in the case of
(C) no THz field, (D) a field of
42.55 THz, (E) a field of 51.61
THz and (F) an enhanced field
of 51.61 THz. The inner insets
show the corresponding bond
length oscillation within 700 fs
of the 600 ps simulation dura-
tion for different cases. Figures
are modified from reference
[52].

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
enough to stimulate the carboxyl group’s carbon-oxygen
bond, further bolstering calcium ion permeation, as expli-
cated in a previous study [51].
Via computational simulations, Bo et al. ascertained that
terahertz radiation induces oscillations in membrane poten-
tial, thereby activating voltage-gated calcium channels, as
indicated in citation [49]. In addition, Guo et al. established
a three-dimensional model of a calcium ion channel and cal-
culated the regulation of the terahertz field on ion movement
[50]. Their pioneering observation documented calcium ions
traversing the channel in picosecond durations, concomi-
tant with terahertz wavelengths. Using Brownian dynamics
simulations, they observed that the ion transport rate through
calcium channels increased proportionally with the intensity
and frequency of applied terahertz waves [50].
In scenarios where the electric field exhibits a frequency of 1
THz and an intensity of 9×108 V/m, an individual calcium ion
can transition from the membrane’s inner facet to its exterior
in a span of 250 ps. In the absence of this applied field, ions
exhibit oscillations predominantly at the nadir of the potential
curve, attesting to the amplifying influence of the terahertz elec-
tric field on calcium channel permeability [50, 51].
Additionally, other research groups have investigated the
influence of terahertz radiation on potassium channels using
advanced molecular dynamics simulations [71, 84]. Adopting
CHARMM-GUI, they integrated the tetramer KcsA channel
within dipalmitoyl phosphatidylcholine (DPPC), saturated
the simulation enclosure with simple point-charged (SPC)
water, and introduced a potassium chloride solution (0.15
mmol/L) into the system for a 400 ps pre-equilibration. This
was instrumental in ascertaining the precise positioning of
proteins and phospholipid molecules, as cited in [84]. Owing
to the vibrational spectrum of the carbonyl group (-C=O)
in the selectivity filter of the potassium channel peaking
approximately at 53.7 THz, the induced resonance effect
could potentially elevate potassium ion permeability [85, 86].
The GROMACS software suite was harnessed for simu-
lations, revealing that terahertz radiation at 53.7 THz not
only hastened potassium ion passage but also modified the
structural attributes of KcsA channels. Specifically, there
was a decline in α-helix structures and an increase in β-folds
and coils, elucidating the terahertz radiation’s impact on the
KcsA channel proteins’ secondary structural configuration,
as depicted in Fig.4A–C [84].
Furthermore, the group discerned the influence of tera-
hertz radiation intensity on hydrogen bond quantity, show-
cased in Fig.4D. Such hydrogen bonds, integral to protein
residues, play a pivotal role in upholding protein folding,
secondary structural elements, molecular recognition, and
overall three-dimensional structural stability. They are
quintessential components of ion channels [62, 68]. The
molecular dynamics simulations unveiled that the ion chan-
nel’s hydrogen bond count incrementally escalated with
prolonged radiation exposure, eventually stabilizing. How-
ever, heightened terahertz wave amplitudes precipitated a
decline in hydrogen bond counts post-stabilization, insinu-
ating attenuated stability of ion channels and heightened
susceptibility in potassium ion permeation [84].
Moreover, the influence of terahertz wave intensity on
potassium ion permeability rates was discerned, as presented
in Fig.4F. The empirical findings indicate a rise in potassium
ion permeation rates concomitant with escalating terahertz
radiation intensities, albeit with an eventual stabilization.
This might be attributed to the electrostatic affinity of channel
proteins towards potassium ions. Sun et al., postulated that
terahertz waves’ facilitative influence on potassium ion per-
meation rates emanates from a resonance interplay between
the terahertz waves and the potassium channel proteins’
carbonyl group, in tandem with the radiation’s cumulative
impact on potassium ions’ Coulombic forces [84].
Hu et al., also adopted the molecular dynamics simula-
tion to introduce terahertz wave radiation as a variable factor
[70]. Through a series of experiments, they delineated the
augmentative effect of external terahertz radiation on KcsA
channel permeability from an ionic current perspective. This
exploration holds profound implications for advancing the
development of artificial molecular sieves and therapeutics
for ion channel-related ailments.
It’s crucial to note that the effect of terahertz waves on
various ion channels is diverse and potentially governed by
intricate mechanisms. Notably, terahertz waves exhibit a
preference for potassium channels, exerting minimal influ-
ence on sodium channels [85]. However, their interaction
with calcium channels displays a dichotomy: they enhance
permeability at subdued intensities but attenuate it at mar-
ginally elevated intensities [49].
This discovery sheds light on the complex interaction
between external electromagnetic fields, specifically tera-
hertz radiation, and ionic channels. Elucidating the mecha-
nisms underlying this phenomenon and its consequences for
cellular function is crucial. As terahertz technology finds
increasing applications in diverse fields such as medical
imaging, material characterization, and telecommunication,
understanding its biological effects is paramount for ensur-
ing its safe and effective utilization. In the face of emerging
electromagnetic technologies, meticulous scrutiny of their
interactions with biological systems is essential to safeguard
human health and maximize their potential benefits.
Neurobiological Applications ofTerahertz Waves
The neurobiological applications of terahertz (THz) waves
have expanded significantly in recent years. THz waves
offer promising avenues for understanding and influencing

Neurosci. Bull.
neuronal behavior and molecular dynamics within the nerv-
ous system.
Behavioral Effects ofTHz Radiation onAnimals
THz radiation’s impact on animal behavior varies with its fre-
quency and intensity. For instance, exposure to certain THz
frequencies induces depressive behaviors and diminishes
rats’ exploratory abilities [87]. Lower frequencies provoke
anxiety, reduce appetite and sleep, and heighten aggression
[88]. These findings underscore the frequency-dependent
behavioral changes in animals caused by THz radiation.
Cellular andMolecular Effects ofTHz Radiation
THz radiation has a significant impact on cellular and
molecular structures within the nervous system [72]. It can
alter nerve cell membrane permeability, potentially through
changes in membrane protein shape and the creation of
hydrophilic pores. THz irradiation causes observable struc-
tural changes in the cell body, axon, and growth cone, par-
ticularly during early neuronal development [72]. This can
disrupt neurite growth cones later on, impacting how neurons
connect. The frequency and power density of THz radiation
are crucial factors—for example, high-power THz radiation
(30mW/cm2) can cause cell death within 2 hours of constant
exposure at a frequency of 2.3THz for 1minute [72].
Biological Mechanisms ofTHz Radiation
Unlike high-energy, damaging electromagnetic radiation
like X-rays and gamma rays, terahertz (THz) waves inter-
act with biological systems through unique mechanisms.
Despite having energy levels as low as a few millielec-
tronvolts (meV), THz waves can induce both thermal [21,
27] and non-thermal effects [30, 54, 85, 89]. Non-thermal
effects include conformational changes in proteins, disrup-
tion or leakage of plasma membranes, and disruption of
DNA double-strand replication or repair. These effects can
lead to diverse biological responses, including alterations in
neurotransmitter expression, modulation of cell membrane
permeability, and induction of cell death [38, 72, 74].
Molecular Basis ofTHz Impacts ontheNervous System
THz wave radiation generates low-frequency resonances in
biomacromolecules, affecting protein spatial conformation
[54, 59, 78] and DNA stability [31, 90]. These resonances
can cause changes in the expression of synaptic-related
Fig. 4 A Change in the number of α-helices. B Change in the num-
ber of coils. C Change in the number of β-folds. D Change in the
number of hydrogen bonds in proteins of the KcsA channel with
different intensities of THz wave. E The model of the K+ channel
established by the team in the experiments. F The number of K+ ions
passing through K+ channels when the THz wave intensity is different
reaches a peak, the field strength of the wave is 0.3 V/nm. Figures are
modified from reference [88].

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
proteins such as SYN and PSD95 in MN9D cells [57],
impacting neuronal functionality and communication. This
suggests that THz radiation has the potential to modulate
key molecular pathways and protein interactions essential
for neuronal health and signal transmission.
The physicochemical properties of THz technology make
it a promising tool for biomedical applications [17, 21, 25].
THz spectroscopy can distinguish different biomolecules
and analyze conformational changes. This technology is
particularly useful in investigating protein conformational
changes and quantifying intermolecular interactions. Addi-
tionally, the THz time-domain system (THz-TDS) is used
in classifying tissues in various disease models, including
amyloid aggregation and neurofibrillary tangles [91]. This
versatility highlights THz technology’s potential in diagnos-
ing and treating neurological conditions.
Classified as non-ionizing because its photons have
extremely low energy, terahertz (THz) radiation is thought to
cause minimal damage to biological tissues or genetic mate-
rial [92]. The frequency range of THz waves encompasses
numerous vibration frequencies of chemical bonds within
biomolecules, crucial in the function domains of various
proteins like ion channels [27]. This may result in nonlinear
resonances within biomolecules, causing significant changes
in their conformation and function and producing nonther-
mal effects on biological systems [54, 57, 85].
Through patch-clamp recordings from neurons in acute
slices of mouse cortex, Liu and colleagues discovered that
THz waves at a frequency of 53.53 THz preferentially
enhance potassium currents (but not sodium currents) in a
nonthermal manner [85] (Fig.5A, B). Given that potassium
channels are vital in the repolarization of action potentials,
increased potassium efflux due to THz wave exposure can
lead to faster and earlier repolarization, resulting in short-
ened action potential durations [85], as illustrated in Fig.5C,
D.
To delve into the molecular dynamics (MD) mechanisms
of THz effects, Liu and colleagues [85] constructed models
of potassium and sodium channels with high ion selectivity
and analyzed the vibration spectrum of the functional chem-
ical bonds in their selectivity filters (–C=O for K+ channels,
–COO− for Na+ channels), as illustrated in Fig.6A-D. They
identified two significant absorption fingerprint peaks for
K+ channels at approximately 34 THz and 53 THz [85].
Notably, these peaks occur just outside the strong absorp-
tion spectrum of water [93, 94] and are distinct from the
fingerprint peaks of –COO− at the selectivity filter of Na+
channels [85], elucidating the selective modulation of K+
channels (but not Na+ channels). This evidence indicates
that the resonantly absorbed energy directly facilitates
the vibration of specific chemical bonds in ion channels,
thereby enhancing their function (Fig.6E–F). With another
absorption fingerprint peak for K+ channels at 34 THz, two
other research groups similarly observed THz effects on
K+ currents [72] and activities in cochlear outer hair cells
and on neuronal spiking activity in behaving pigeons [94],
respectively.
The brain continuously performs complex computations
[95–98] to encode sensory information and guide behavioral
responses. Investigating the impact of THz wave stimulation
on sensorimotor functions, Liu and colleagues [85] applied
a 53.53 THz wave to the brains of larval zebrafish, position-
ing the laser fiber tip over 300 µm away from the larval
skin to avoid thermal effects. They found that the THz wave
suppressed C-start escape responses triggered by weak sen-
sory stimuli but enhanced those evoked by strong stimuli, as
illustrated in Fig.7. These behavioral findings align with the
gain modulatory effect of THz waves on neuronal spiking
activity [85] . In a similar vein, Yang’s group demonstrated
that a 34.88 THz wave also regulates ongoing neuronal spik-
ing activity in awake, behaving pigeons [94]. These findings
suggest that THz wave radiation at both 53.53 and 34.88
THz could be an effective method for modulating neural
circuit functions. Unlike electrical stimulation, which acti-
vates axon fibers in the stimulated region, THz waves do
not induce action potential generation in axons, indicating
high spatial selectivity. Furthermore, THz wave stimulation
exhibits spatial selectivity and long-distance regulatory
effects on neuronal signaling [85], highlighting its potential
to avoid tissue damage.
Overall, the diverse effects of THz waves on cellular [99]
and molecular dynamics [100, 101] in the nervous system
underscore their potential in medical and biological research.
Understanding these interactions can lead to advancements
in diagnosing and treating neurological conditions [102].
Future research should focus on standardizing experimen-
tal parameters of THz radiation to ensure reproducibility
and comparability of experiments and explore the systemic
impacts of THz radiation on biomacromolecules, gene net-
works, and signaling pathways.
In summary, the molecular basis of THz impacts on the
nervous system and its diverse applications in neuroscience
underscore THz technology’s potential in medical and bio-
logical research. Future studies should aim to standardize
experimental parameters and explore systemic impacts on
biomacromolecules, gene networks, and signaling pathways,
paving the way for significant advancements in neuroscien-
tific understanding and therapy.
Discussion ontheInteraction Mechanism
betweenTerahertz Waves andIon Channels
Terahertz (THz) radiation has emerged as a crucial factor
influencing ion channels, and recent research has unveiled a
potential bidirectional interaction where ion channels may

Neurosci. Bull.
emit terahertz radiation during ion transportation, fostering
heightened scientific interest.
According to a hypothesis put forward by Liu and his
colleagues, terahertz waves, under specific conditions, can
interact with organisms and could be pivotal in either treat-
ing or inducing diseases [103]. Simultaneously, the oscilla-
tion frequency of certain ions falls within the terahertz range
[4]. The phenomenon of ion channels producing terahertz
waves may be tied to the oscillation in the terahertz band
resulting from transiting ions.
Wang et al. used Brownian dynamics simulations to
investigate the radiation spectrum of calcium ions within
channels. Their findings indicate that these ions can gener-
ate terahertz radiation, particularly around 16.9 THz [50].
Fourier analysis of the electric field produced by calcium ion
movement confirms this emission spectrum. This research
provides strong theoretical evidence for the ability of ions to
generate terahertz radiation within ion channels.
Using terahertz spectroscopy, Wang and Gong’s teams
examined the diffusion and penetration of ions within the
ion channel, taking into account the ions’ zero-point energy
in the potential well and the quantum tunneling effect [71].
Wang and Gong’s collaboration developed a theoretical
framework known as the terahertz (THz) trapped ion model
[71], tailored for the selectivity filters in potassium ion chan-
nels, like KcsA. This model is based on principles from den-
sity functional theory, a method used to calculate the forces
and energies of ions in ion channels. In this model, ions are
thought of as being in a ‘potential well’, a kind of energy
landscape where they display behaviors akin to quantum par-
ticles. Just like particles in quantum mechanics, ions have
specific, fixed energy levels they can occupy. This is similar
to the way musical notes are distinct and separate on a scale.
Therefore, ions can only exist in these specific energy states,
which are clearly defined and separate from one another.
To make this concept more accessible, imagine ions mov-
ing up or down a staircase, where each step represents a dis-
tinct energy level. In this terahertz (THz) trapped ion model,
as ions move or vibrate within the selectivity filters of potas-
sium channels, their oscillations align with the energy levels
characteristic of terahertz radiation. This means the ions can
vibrate at frequencies that fall within the terahertz range, a
Fig. 5 A Schematic of THz and a somatic nucleated patch from a
pyramidal cell (PC) in a prefrontal cortical slice. Note the THz fiber
tip is placed at a distance from the cell (also the nucleated patch) to
ensure no temperature increase at the recording site. (B, left) repre-
sentative families of K+ currents in control (blue) and during THz
stimulation (orange). (B, right) I-V curves of K+ currents. C Sche-
matic of a whole-cell recording from a PC. (D, left) Representative
action potential waveforms before and during THz stimulation. (D,
right) comparison of action potential half-width before and during
THz stimulation. **P <0.01 and ***P <0.001; paired Student’s t-test.
Figures are modified from reference [62].

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
Fig. 6 A and C, left, Specific peptide structure of the ion selectivity
filter. The red and cyan balls indicate the critically functional atoms
of oxygen and carbon of the filter on the protein chains (gray rib-
bons); orange and blue denote individual K+ and Na+, respectively.
(A and C, right) Side (Upper) and top (Lower) views of the modeled
filter region in molecular dynamics simulations. The cyan tube and
two sheets represent the channel and its supporting bilayered mem-
brane, respectively. The black arrows together with the red and blue
curves indicate the added THz. B and D Selectivity efficiencies of
modeled K+ (B) and Na+ (D) channels. E Effects of THz on ion flow
through the channels. F Vibration spectra of modeled K+ (orange)
and Na+ (blue) channels. The peaks at 53.7 and 48.2 THz are contrib-
uted by the –C=O and –COO− vibrations, respectively. Figures are
modified from reference [62].
Fig. 7 A A representative larval zebrafish showing the initial move-
ment of a C-start response induced by an aversive sensory stimulus.
B Video-captured tail positions (presented in chronological order
by gradient color) in single trials with sensory stimulation at the
given power densities. Note that THz inhibits C-start responses to
weak stimuli but enhances those to strong stimuli. C Sensory stim-
ulation intensity-dependent tail movement (the total tail-swept area,
maximum tail angle, the maximum angular velocity, and the escape
response rate) and the regulation by THz. Error bars represent the
SEM. Figures are modified from reference [62].

Neurosci. Bull.
segment of the electromagnetic spectrum that lies between
microwaves and infrared light. This connection reveals how
the subtle movements of ions could be linked to the genera-
tion and interaction with terahertz radiation, shedding light
on a possible quantum mechanical relationship between bio-
logical processes and terahertz radiation.
Through this framework, they demonstrated that potas-
sium ions oscillating within the selectivity filter produce
radiation within the 2.0 to 6.5 THz frequency range. Such
findings affirm the theoretical foundation for a terahertz ion
trap existing within the selectivity filter, illuminating the
quantum theory-based mechanisms that underlie ion channel
permeation. This breakthrough offers a deeper understand-
ing of how ions navigate through cellular structures, high-
lighting the significant role that quantum effects play in the
functioning of biological systems and their interaction with
terahertz radiation [71].
Furthermore, recent studies [104, 105] also highlighted
the influence of THz radiation on neurons, activating
action potentials by affecting sodium and potassium. When
exposed to THz pulses, Na+ channels open, leading to an
influx of Na+ that causes the membrane potential to reach
the threshold for depolarization. Following this, K+ chan-
nels open, allowing K+ to exit the cell, while Na+ chan-
nels close, resulting in the repolarization of the membrane
potential back to its resting state. This process allows THz
pulses to continuously trigger action potentials in the nerve
cells. Liu’s group [4, 103, 106] conducted theoretical studies
demonstrating that neural signals consist of low-frequency
action potentials and high-frequency electromagnetic fields,
with frequencies in the terahertz (THz) and infrared ranges.
Despite the slow changes in the high-frequency signals’
envelopes, both types of signals travel at identical speeds.
Despite these advancements, the mechanism of inter-
action between ion channels and terahertz waves remains
unclear, necessitating further comprehensive experimental
and theoretical studies. Additionally, weak photon emis-
sions have been detected in living cells [107], biological
tissue sections [108], and living organisms [109]. However,
these emissions generally occur within the UVA (Ultraviolet
A), visible light, and near-infrared spectra, which are far
removed from the terahertz band. Due to their significantly
different emission mechanisms [110], these phenomena are
not discussed further here.
Summary andProspect
Over the last five decades, terahertz (THz) technology has
significantly evolved but remains underexplored due to
research limitations. The interaction of THz waves with
biological matter is primarily studied in weak field condi-
tions [71], with water’s strong absorption of THz waves
complicating cellular studies due to the aqueous nature of
both intra and extracellular environments. Research on the
impact of THz exposure on ion channels, crucial for cell
membrane functions, relies on computational simulations
using tools like GROMACS [111] and CHARMM-GUI
[112, 113], providing insights into the structural and func-
tional dynamics of ion channels.
The discussion highlights key findings: (1) Terahertz
waves can modify macromolecular structures and cell mem-
branes by matching their vibrational frequencies [107]. (2)
Ion channels resonate with specific terahertz frequencies,
causing structural and functional changes, with the effects
on ions and channels creating a combined response [108].
(3) While terahertz waves are non-ionizing, their absorption
by water-rich tissues can cause heating or damage, yet cer-
tain frequencies may have therapeutic potential, notably for
hearing [109]. (4) Ion channels might emit terahertz waves
during ion transport due to oscillations [110].
Future Research Directions and Unresolved Questions:
The precise nature and mechanisms of THz wave interac-
tions with ion channels during ion transport are still to be
fully understood, necessitating detailed investigations.
THz waves’ strong absorption by water molecules chal-
lenges their penetration into biological tissues, with the
effects on specific cell types like neurons and myocardial
cells requiring further research for potential clinical appli-
cations [114].
The influence of THz waves on ionic transport manage-
ment and its potential link to quantum coherence phenomena
presents an opportunity to connect classical and quantum
theories [115].
The ability of THz waves to selectively modulate nerve
impulses points to possible therapeutic uses for neurological
conditions [116, 117], an area that is still largely unexplored.
Research in the THz-ion channel field is currently limited
to a few groups, focusing mainly on calcium ion channels,
with minimal exploration into potassium and sodium ion
channels, indicating a broad area for future exploration.
In conclusion, advances have been made in deciphering
how terahertz (THz) waves interact with ion channels and
various molecular entities. Nonetheless, there’s a signifi-
cant need for further research to assess their effects on the
physical and behavioral traits of both animals and humans.
This highlights the critical role of in-depth phenomic stud-
ies [118–120] in probing into the subtleties of THz wave
influences, with the goal of uncovering fundamental mecha-
nisms and assessing possible therapeutic potentials [116,
117]. Such exploration could expand to encompass a wider
range of biological subjects, enriching our understanding of
THz wave biology.
Acknowledgements Thanks for the support from the Science and
Technology Innovation 2030 - Brain Science and Brain-Inspired

Y. Liu et al.: Progress of the Impact of Terahertz Radiation on Ion Channel Kinetics
Intelligence Project (2021ZD0201301 and 2021ZD0200204) and
STI2030-Major Projects (2021ZD0202500), the National Natural
Science Foundation of China (U20A20221, 32130044, T2241002,
32200807), the Shanghai Municipal Science and Technology Major
Project (2018SHZDZX01 and 2021SHZDZX0103) and ZJLab, Shang-
hai Municipal Science and Technology Committee of Shanghai out-
standing academic leaders plan (21XD1400400, 21XD1400100).
Conflict of interest The authors declare that there is no conflict of
interest.
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