High Frequency Terahertz Stimulation Alleviates Neuropathic Pain by Inhibiting the Pyramidal Neuron Activity in the Anterior Cingulate Cortex of mice
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Peng et al. reported important findings that 36THz high-frequency terahertz stimulation (HFTS) could suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channels. The significance of the findings in this paper is that chronic pain remains a significant medical problem, and there is a need to find non-pharmacological interventions for treatment. The authors present convincing evidence that high-frequency stimulation of the anterior cingulate cortex can alter neuronal activity and improve sensory pain behaviors in mice.
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Abstract
Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7– 10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximate 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex through enhancing the voltage-gated K + (Kv) conductance. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising application in other nervous system diseases.
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eLife assessment
Peng et al. reported important findings that 36THz high-frequency terahertz stimulation (HFTS) could suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channels. The significance of the findings in this paper is that chronic pain remains a significant medical problem, and there is a need to find non-pharmacological interventions for treatment. The authors present convincing evidence that high-frequency stimulation of the anterior cingulate cortex can alter neuronal activity and improve sensory pain behaviors in mice.
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Reviewer #1 (Public Review):
In this manuscript, by using simulation, in vitro and in vivo electrophysiology, and behavioral tests, Peng et al. nicely showed a new approach for the treatment of neuropathic pain in mice. They found that terahertz (THz) waves increased Kv conductance and decreased the frequency of action potentials in pyramidal neurons in the ACC region. Behaviorally, terahertz (THz) waves alleviated neuropathic pain in the mouse model. Overall, this is an interesting study. The experimental design is clear, the data is presented well, and the paper is well-written. I have a few suggestions.
(1) The authors provide strong theoretical and experimental evidence for the impact of voltage-gated potassium channels by terahertz wave frequency. However, the modulation of action potential also relies on non-voltage-dependent ion …
Reviewer #1 (Public Review):
In this manuscript, by using simulation, in vitro and in vivo electrophysiology, and behavioral tests, Peng et al. nicely showed a new approach for the treatment of neuropathic pain in mice. They found that terahertz (THz) waves increased Kv conductance and decreased the frequency of action potentials in pyramidal neurons in the ACC region. Behaviorally, terahertz (THz) waves alleviated neuropathic pain in the mouse model. Overall, this is an interesting study. The experimental design is clear, the data is presented well, and the paper is well-written. I have a few suggestions.
(1) The authors provide strong theoretical and experimental evidence for the impact of voltage-gated potassium channels by terahertz wave frequency. However, the modulation of action potential also relies on non-voltage-dependent ion channels. For example, I noticed that the RMP was affected by THz application (Figure 3F) as well. As the RMP is largely regulated by the leak potassium channels (Tandem-pore potassium channels), I would suggest testing whether terahertz wave photons have also any impact on the Kleak channels as well.
(2) The activation curves of the Kv currents in Figure 2h seem to be not well-fitted. I would suggest testing a higher voltage (>100 mV) to collect more data to achieve a better fitting.
(3) In the part of behavior tests, the pain threshold increased after THz application and lasted within 60 mins. I suggest conducting prolonged tests to determine the end of the analgesic effect of terahertz waves.
(4) Regarding in vivo electrophysiological recordings, the post-HFTS recordings were acquired from a time window of up to 20 min. It seems that the HFTS effect lasted for minutes, but this was not tested in vitro where they looked at potassium currents. This long-lasting effect of HFTS is interesting. Can the authors discuss it and its possible mechanisms, or test it in slice electrophysiological experiments?
(5) How did the authors arrange the fiber for HFTS delivery and the electrode for in vivo multi-channel recordings? Providing a schematic illustration in Figure 4 would be useful.
(6) Some grammatical errors should be corrected.
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Reviewer #2 (Public Review):
Summary:
In this manuscript, Peng et al., reported that 36THz high-frequency terahertz stimulation (HFTS) can suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channel. The authors also demonstrated the effectiveness of using 36THz HFTS for treating neuropathic pain.
Strengths:
The manuscript is well written and the conclusions are supported by robust results. This study highlighted the potential of using 36THz HFTS for neuromodulation.
Weaknesses:
More characterization of HFTS is needed, so the readers can have a better assessment of the potential usage of HFTS in their own applications.
(1) It would be very helpful to estimate the volume of tissue that can be influenced by HFTS. It is not clear how 15 mins HFTS was chosen for this functional study. Does a …
Reviewer #2 (Public Review):
Summary:
In this manuscript, Peng et al., reported that 36THz high-frequency terahertz stimulation (HFTS) can suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channel. The authors also demonstrated the effectiveness of using 36THz HFTS for treating neuropathic pain.
Strengths:
The manuscript is well written and the conclusions are supported by robust results. This study highlighted the potential of using 36THz HFTS for neuromodulation.
Weaknesses:
More characterization of HFTS is needed, so the readers can have a better assessment of the potential usage of HFTS in their own applications.
(1) It would be very helpful to estimate the volume of tissue that can be influenced by HFTS. It is not clear how 15 mins HFTS was chosen for this functional study. Does a longer time have a stronger effect? A better characterization of the relationship between the stimulus duration of HFTS and its beneficial effects would be very useful.
(2) How long does the behavioral effect last after 15 minutes of HFTS? Figure 5b only presents the behavioral effect for one hour, but the pain level is still effectively reduced at this time point. The behavioral measurement should last until pain sensitization drops back to pre-stim level.
(3) Although the manuscript only tested in ACC, it will also be useful to demonstrate the neural modulation effect on other brain regions. Would 36THz HFTS also robustly modulate activities in other brain regions? Or are different frequencies needed for different brain regions?
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Reviewer #3 (Public Review):
Summary:
This manuscript by Peng et al. presents intriguing data indicating that high-frequency terahertz stimulation (HFTS) of the anterior cingulate cortex (ACC) can alleviate neuropathic pain behaviors in mice. Specifically, the investigators report that terahertz (THz) frequency stimulation widens the selectivity filter of potassium channels thereby increasing potassium conductance and leading to a reduction in the excitability of cortical neurons. In voltage clamp recordings from layer 5 ACC pyramidal neurons in acute brain slice, Peng et al. show that HFTS enhances K current while showing minimal effects on Na current. Current clamp recording analyses show that the spared nerve injury model of neuropathic pain decreases the current threshold for action potential (AP) generation and increases evoked AP …
Reviewer #3 (Public Review):
Summary:
This manuscript by Peng et al. presents intriguing data indicating that high-frequency terahertz stimulation (HFTS) of the anterior cingulate cortex (ACC) can alleviate neuropathic pain behaviors in mice. Specifically, the investigators report that terahertz (THz) frequency stimulation widens the selectivity filter of potassium channels thereby increasing potassium conductance and leading to a reduction in the excitability of cortical neurons. In voltage clamp recordings from layer 5 ACC pyramidal neurons in acute brain slice, Peng et al. show that HFTS enhances K current while showing minimal effects on Na current. Current clamp recording analyses show that the spared nerve injury model of neuropathic pain decreases the current threshold for action potential (AP) generation and increases evoked AP frequency in layer 5 ACC pyramidal neurons, which is consistent with previous studies. Data are presented showing that ex-vivo treatment with HFTS in slice reduces these SNI-induced changes to excitability in layer 5 ACC pyramidal neurons. The authors also confirm that HFTS reduces the excitability of layer 5 ACC pyramidal neurons via in vivo multi-channel recordings from SNI mice. Lastly, the authors show that HFTS is effective at reducing mechanical allodynia in SNI using both the von Frey and Catwalk analyses. Overall, there is considerable enthusiasm for the findings presented in this manuscript given the need for non-pharmacological treatments for pain in the clinical setting.
Strengths:
The authors use a multifaceted approach that includes modeling, ex-vivo and in-vivo electrophysiological recordings, and behavioral analyses. Interpretation of the findings is consistent with the data presented. This preclinical work in mice provides new insight into the potential use of directed high-frequency stimulation to the cortex as a primary or adjunctive treatment for chronic pain.
Weaknesses:
There are a few concerns noted that if addressed, would significantly increase enthusiasm for the study.
(1) The left Na current trace for SNI + HFTS in Figure 2B looks to have a significant series resistance error. Time constants (tau) for the rate of activation and inactivation for Na currents would be informative.
(2) It is unclear why an unpaired t-test was performed for paired data in Figure 2. Also, statistical methods and values for non-significant data should be presented.
(3) It would seem logical to perform HFTS on ACC-Pyr neurons in acute slices from sham mice (i.e. Figure 3 scenario). These experiments would be informative given the data presented in Figure 4.
(4) As the data are presented in Figure 4g, it does not seem as if SNI significantly increased the mean firing rate for ACC-Pyr neurons, which is observed in the slice. The data were analyzed using a paired t-test within each group (sham and SNI), but there is no indication that statistical comparisons across groups were performed. If the argument is that HFTS can restore normal activity of ACC-Pyr neurons following SNI, this is a bit concerning if no significant increase in ACC-Pyr activity is observed in in-vivo recordings from SNI mice.
(5) The authors indicate that the effects of HFTS are due to changes in Kv1.2. However, they do not directly test this. A blocking peptide or dendrotoxin could be used in voltage clamp recordings to eliminate Kv1.2 current and then test if this eliminates the effects of HFTS. If K current is completely blocked in VC recordings then the authors can claim that currents they are recording are Kv1.1 or 1.2.
(6) The ACC is implicated in modulating the aversive aspect of pain. It would be interesting to know whether HFTS could induce conditioned place preference in SNI mice via negative reinforcement (i.e. alleviation of spontaneous pain due to the injury). This would strengthen the clinical relevance of using HFTS in treating pain.
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