Nat Biomed Eng︱Utilizes infrared light through the brain to modulate deep brain neural activity

Written by ︱ Wu Xiang, edited by Hong Guosong ︱ Wang Sizhen The brain, as one of the most mysterious organs of human beings, plays the role of the manager of the nervous system in the human body
.

How the brain works, how different brain regions communicate, and how the brain's neuron activity and behavior are linked have always been difficult problems for neuroscientists to solve
.

Neuromodulation technology allows researchers to selectively excite or inhibit a certain brain region or a certain type of neurons, and then study the role of these neurons by observing the changes caused by neuromodulation [1-3]
.

In addition to the earliest electrical stimulation method [4], the optogenetics technology that has developed rapidly in recent years can activate photosensitive ion channel proteins with millisecond pulses of visible light, so as to achieve the purpose of regulating neural activity [1-3]
.

However, both electric fields and visible light are strongly attenuated when propagating in the brain [5-7], so traditional electrical or optogenetic methods often require invasive electrodes or optical fibers to be implanted in the brain
.

These permanent brain implants not only cause brain tissue damage, but also physically restrain the subject's head, thereby altering the subject's expected behavioral responses [8]
.

 On March 21, 2022, the research group of Hong Guosong of Stanford University and the research group of Pu Kanxi of Nanyang Technological University of Singapore jointly published a paper entitled "Tether-free photothermal deep-brain stimulation in freely behaving mice via wide" in Nature Biomedical Engineering.
-field illumination in the near-infrared-II window", reported an electromagnetic wave in the near-infrared region II (NIR-II window, 1000-1700 nm) band that can penetrate tissue through the intact scalp and Skull, a technique for modulating deep-brain neuronal activity in freely moving mice
.

The inspiration for this work comes from the research work of David Julius, one of the 2021 Nobel Prize winners in medicine, on the molecular mechanism of human temperature perception
.

Julius discovered that human perception of different temperatures originates from a group of membrane proteins called transient receptor potential (TRP) channels
.

Different TRP proteins respond to different ranges of temperature and control the entry and exit of ions inside and outside the membrane, thereby converting temperature information into electrical signals common between cells [9]
.

Among them, an ion channel called TRPV1 (transient receptor potential cation channel subfamily V member 1) was the first protein in the TRP family discovered by Julius [10]
.

What's more interesting is that the research work after Julius showed that the molecular mechanism of the rattlesnake's induction of infrared rays is also the TRP protein family [11]
.

Specifically, the TRP protein, located in a special organ called the buccal fossa, senses the thermal effects of infrared radiation, allowing it to perceive thermal images that are invisible to the human visual system
.

Figure 1 (a) Schematic diagram of NIR-II neuromodulation technology; (b) schematic diagram of MINDS design; (c) brightfield photo and thermal image of coronal section of mouse brain under NIR-II illumination
.

(Photo credit: Wu, X et al.
, Nat Biomed Eng, 2022) Inspired by these works, researchers from two research groups proposed a hypothesis: whether the mechanism of natural rattlesnakes sensing infrared light can be used to make mammalian brains.
The inner neurons express TRP protein, so as to achieve the purpose of regulating deep brain neural activity with near-infrared light (Fig.
1a)? Compared with visible light used in traditional optogenetics, near-infrared light has a deeper penetration depth in highly scattered biological tissues, so it is more suitable as an energy transfer medium in optical neuromodulation technology [12]
.

Specifically, the researchers found through simulation calculations that NIR-II light at around 1064-nm has the deepest penetration in the brain in the entire visible to near-infrared spectrum
.

However, even NIR-II light, which penetrates deep into tissue, is still attenuated in brain tissue by scattering and absorption, with the absorbed portion being converted to heat
.

Therefore, to excite TRPV1-expressing neurons located in the deep brain, high-intensity NIR-II light needs to be incident from above
.

These high-intensity NIR-II light, absorbed by the superficial brain regions, produces a much higher temperature rise than the deep brain regions, which in turn alters neuronal firing patterns and even causes irreversible thermal damage to brain tissue [13,14]
.

 One solution to this problem is to make neurons in the deep brain more sensitive to NIR-II light than cells in the superficial brain regions
.

To this end, researchers from the two groups designed a nanoconductor called MINDS (macromolecular infrared nanotransducers for deep brain stimulation) (Fig.
1b) to efficiently absorb NIR-II light penetrating into the deep brain.
and convert it into heat
.

Specifically, the photothermal conversion efficiency of MINDS at 1064-nm is as high as 71%
.

The researchers experimentally demonstrated that MINDS located 5 mm deep in the brain produced higher local warming than superficial brain regions under NIR-II illumination (Fig.
1c)
.

The superior photothermal properties of MINDS can make localized TRPV1-expressing neurons more sensitive to NIR-II, thereby enabling NIR-II neuromodulation within a safe radiation range
.

Figure 2 (a) Schematic diagram of TRPV1 transfection and MINDS injection experiments in VTA dopamine neurons; (b) Y-maze conditioned place preference experiment photos; (c) Place preference distribution of mice under different experimental conditions
.

(Source: Wu, X et al.
, Nat Biomed Eng, 2022) To verify the feasibility of this NIR-II neuromodulation technology, the researchers selectively located the ventral tegmental area (VTA) of the mouse brain.
TRPV1 channel protein was transfected in the dopamine neurons of 100%, and MINDS was injected into the same brain region (Fig.
2a)
.

These dopamine neurons located in the VTA play a very important role in the reward circuit of the brain [2]
.

In the experiment, the researchers used the conditioned place preference experiment in the Y-maze to study the effect of NIR-II neuromodulation
.

Specifically, the researchers marked different black and white stripes on the inner walls of the ends of the three arms of the Y maze, and irradiated NIR-II light only at the end of a certain arm (Fig.
2b).

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It is worth noting that in the experiment, the light source of NIR-II was placed about one meter above the mouse's head, and no other devices were placed near the mouse's head
.

After three consecutive days of training, the mice in the experimental group learned to establish a link between NIR-II-induced dopamine secretion (i.
e.
, reward) and the streak pattern on the inner wall of the NIR-II-irradiated terminal A strong preference for the position of the NIR-II irradiated tip was shown in the test
.

In contrast, control mice lacking TRPV1 transfection or MINDS injection did not exhibit similar place preference
.

These experimental results, as well as the electrophysiological and tissue section data in the article, demonstrate the feasibility of the NIR-II deep-brain neuromodulation technology
.

Conclusions and discussions, inspirations and prospects, the NIR-II neuromodulation technique reported in this latest report has many advantages over traditional electrode- or fiber-optic-based neurostimulation methods
.

First, this technique uses light at 1064 nm, which penetrates the deepest in the brain for the entire visible to near-infrared spectrum, thus eliminating the unavoidable permanent brain implants and their resulting brain tissue in traditional optogenetics damage
.

Second, the superior NIR-II absorption and photothermal properties of MINDS allow NIR-II light in the safe radiation range to be sufficient as a medium for deep brain neuromodulation
.

In addition, NIR-II's nearly lossless propagation in air allows the light source to be placed at nearly any distance above the subject's head, thereby eliminating the physical constraints of traditional electrical or optogenetic methods on the subject's head
.

Despite the many advantages mentioned above, there is room for improvement in this newly reported technique
.

First, the response time of NIR-II neuromodulation technology is a few seconds, so this technology is not suitable for studying neurological problems with time scales on the millisecond scale
.

Nonetheless, many behavioral phenomena and neurological disorders occur on time scales of days or years, and other neuromodulation techniques (such as chemical genetics) with response times on the minute scale are also under study in neurology have been widely used
.

Therefore, this NIR-II neuromodulation technique, which eliminates brain implants and physical constraints, is more suitable for behavioral experiments involving multi-object social interactions
.

Additionally, although this technique is non-invasive in modulating neural activity, transfection of the TRPV1 channel protein and injection of MINDS still require invasive brain surgery
.

This could be improved by future transfection and nanomaterial delivery methods through the blood circulation
.

 In conclusion, this latest work reports the use of NIR-II light through the intact scalp and skull to modulate TRPV1 channel protein-expressing neurons in the deep brain of mice and sensitized by MINDS
.

As an extension of traditional optogenetics, this technique offers the possibility of neuromodulation in multi-subject social interaction behavioral experiments
.

Link to the original text: https://doi.
org/10.
1038/s41551-022-00862-w The first author Wu Xiang (the second from the left in the second row), the corresponding author Hong Guosong (the first from the left in the second row) (Photo provided by: Hong Guosong Laboratory) Selected previous articles [1] Neurosci Bull Review︱ Research progress, problems and prospects of humoral biomarkers in Alzheimer's disease [2] Current Biology Achievement: H2 receptor-dependent medial septal histaminergic circuit【3】Nat Commun︱Guo Ming’s team discovered a new mechanism of mitochondrial fission and a new target for the prevention and treatment of Parkinson’s disease【4】Front Cell Neurosci︱Shi Peng/Liu Zhen’s research group Collaborated to reveal the common molecular mechanism of sensorineural hearing loss caused by multiple factors 【5】Cell Death Dis︱Li Xian’s group revealed the role of oligodendrocyte precursor ferroptosis in white matter damage after cerebral hemorrhage 【6】Front Mol Neurosci ︱ Gao Shangbang’s research group analyzed the composition and molecular mechanism of motor neuron oscillators [7] Nat Neurosci review ︱ Two-photon holographic optogenetics technology to detect neural coding [8] Mol Psychiatry Effects in a dysregulated mouse model【9】Science︱Mice rapid eye movement sleep is modulated by basolateral amygdala dopamine signaling【10】Nat Neurosci︱Amygdala and anterior cingulate neuroimmunity and synapses in patients with bipolar disorder Relevant pathway downgrading high-quality scientific research training courses recommended [1] Scientific research skills︱The 4th near-infrared brain function data analysis class (online: 2022.
4.
18~4.
30) [2] Scientific research skills︱Introduction to Magnetic Resonance Brain Network Analysis (online) : 2022.
4.
6~4.
16)【3】Training Course︱Scientific Research Mapping·Academic Image Special Training【4】Seminar on Single-Cell Sequencing and Spatial Transcriptomics Data Analysis (2022.
4.
2-3 Tencent Online) References (swipe up and down to view ) 1, Fenno, L.
, Yizhar, O.
& Deisseroth, K.
The development and application of optogenetics.
Annu.
Rev.
Neurosci.
34, 389–412 (2011).
2, Tsai, H.
-C.
et al.
Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.
Science 324, 1080–1084 (2009).
3, Montgomery, KL et al.
Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.
Nat.
Methods 12, 969–974 (2015).
4, Lozano, AM et al.
Deep brain stimulation: current challenges and future directions.
Nat.
Rev.
Neurol.
15, 148–160 (2019).
5, Hong, G.
& Lieber, CM Novel electrode technologies for neural recordings.
Nat.
Rev.
Neurosci.
20, 330–345 (2019).
6, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 (2017).
7, Ledesma, HA et al.
An atlas of nano-enabled neural interfaces.
Nat.
Nanotechnol.
14, 645–657 (2019).
8, Kim, T.
-I.
et al.
Injectable,cellular-scale optoelectronics with applications for wireless optogenetics.
Science 340, 211–216 (2013).
9, Julius, D.
TRP channels and pain.
Annu.
Rev.
Cell Dev.
Biol.
29, 355-384 (2013).
10 , Caterina, M.
, Rosen, T.
, Tominaga, M.
et al.
A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441 (1999).
11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 ( 2017).
13, Owen, SF, Liu, MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Plate making︱Sizhen Wang End of this articleScience 340, 211–216 (2013).
9, Julius, D.
TRP channels and pain.
Annu.
Rev.
Cell Dev.
Biol.
29, 355-384 (2013).
10, Caterina, M.
, Rosen, T.
, Tominaga, M.
et al.
A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441 (1999).
11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu , MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108 –1113 (2020).
Plate making︱Wang Sizhen End of this articleScience 340, 211–216 (2013).
9, Julius, D.
TRP channels and pain.
Annu.
Rev.
Cell Dev.
Biol.
29, 355-384 (2013).
10, Caterina, M.
, Rosen, T.
, Tominaga, M.
et al.
A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441 (1999).
11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu , MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108 –1113 (2020).
Plate making︱Wang Sizhen End of this articleBiol.
29, 355-384 (2013).
10, Caterina, M.
, Rosen, T.
, Tominaga, M.
et al.
A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441 ( 1999).
11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu, MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14 , Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paperBiol.
29, 355-384 (2013).
10, Caterina, M.
, Rosen, T.
, Tominaga, M.
et al.
A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441 ( 1999).
11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat.
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu, MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14 , Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paper11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat .
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu, MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paper11, Gracheva, EO et al.
Molecular basis of infrared detection by snakes.
Nature 464, 1006–1011 (2010).
12, Hong, G.
, Antaris, AL & Dai, H.
Near-infrared fluorophores for biomedical imaging.
Nat .
Biomed.
Eng.
1, 0010 (2017).
13, Owen, SF, Liu, MH & Kreitzer, AC Thermal constraints on in vivo optogenetic manipulations.
Nat.
Neurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paperNeurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paperNeurosci.
22, 1061–1065 (2019).
14, Nelidova, D.
et al.
Restoring light sensitivity using tunable near-infrared sensors.
Science 368, 1108–1113 (2020).
Edition ︱Sizhen Wang End of this paper