Contralesional Anodal Transcranial Direct Current Stimulation Promotes Intact Corticospinal Tract Axonal Sprouting and Functional Recovery After Traumatic Brain Injury in Mice.

BACKGROUND: Anodal transcranial direct current stimulation (AtDCS), a neuromodulatory technique, has been applied to treat traumatic brain injury (TBI) in patients and was reported to promote functional improvement. We evaluated the effect of contralesional AtDCS on axonal sprouting of the intact corticospinal tract (CST) and the underlying mechanism in a TBI mouse model to provide more preclinical evidence for the use of AtDCS to treat TBI. METHODS: TBI was induced in mice by a contusion device. Then, the mice were subjected to contralesional AtDCS 5 days per week followed by a 2-day interval for 7 weeks. After AtDCS, motor function was evaluated by the irregular ladder walking, narrow beam walking, and open field tests. CST sprouting was assessed by anterograde and retrograde labeling of corticospinal neurons (CSNs), and the effect of AtDCS was further validated by pharmacogenetic inhibition of axonal sprouting using clozapine-N-oxide (CNO). RESULTS: TBI resulted in damage to the ipsilesional cortex, while the contralesional CST remained intact. AtDCS improved the skilled motor functions of the impaired hindlimb in TBI mice by promoting CST axon sprouting, specifically from the intact hemicord to the denervated hemicord. Furthermore, electrical stimulation of CSNs significantly increased the excitability of neurons and thus activated the mechanistic target of rapamycin (mTOR) pathway. CONCLUSIONS: Contralesional AtDCS improved skilled motor following TBI, partly by promoting axonal sprouting through increased neuronal activity and thus activation of the mTOR pathway.

Adjunct Methods for Alzheimer's Disease Detection: A Review of Auditory Evoked Potentials.

The auditory afferent pathway as a clinical marker of Alzheimer's disease (AD) has sparked interest in investigating the relationship between age-related hearing loss (ARHL) and AD. Given the earlier onset of ARHL compared to cognitive impairment caused by AD, there is a growing emphasis on early diagnosis and intervention to postpone or prevent the progression from ARHL to AD. In this context, auditory evoked potentials (AEPs) have emerged as a widely used objective auditory electrophysiological technique for both the clinical diagnosis and animal experimentation in ARHL due to their non-invasive and repeatable nature. This review focuses on the application of AEPs in AD detection and the auditory nerve system corresponding to different latencies of AEPs. Our objective was to establish AEPs as a systematic and non-invasive adjunct method for enhancing the diagnostic accuracy of AD. The success of AEPs in the early detection and prediction of AD in research settings underscores the need for further clinical application and study.

A brain-tumor neural circuit controls breast cancer progression in mice.

Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeMCRH neurons and the CeMCRH→lateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeMCRH neurons and the CeMCRH→LPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeMCRH→LPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve-derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.

Prelimbic area to lateral hypothalamus circuit drives social aggression.

Controlling aggression is a vital skill in social species such as rodents and humans and has been associated with the medial prefrontal cortex (mPFC). In this study, we showed that during aggressive behavior, the activity of GABAergic neurons in the prelimbic area (PL) of the mPFC was significantly suppressed. Specific activation of GABAergic PL neurons significantly curbed male-to-male aggression and inhibited conditioned place preference (CPP) for aggression-paired contexts, whereas specific inhibition of GABAergic PL neurons brought about the opposite effect. Moreover, GABAergic projections from PL neurons to the lateral hypothalamus (LH) orexinergic neurons mediated aggressive behavior. Finally, directly modulated LH-orexinergic neurons influence aggressive behavior. These results suggest that GABAergic PL-orexinergic LH projection is an important control circuit for intermale aggressive behavior, both of which could be targets for curbing aggression.

Transcranial direct current stimulation regulates phenotypic transformation of microglia to relieve neuropathic pain induced by spinal cord injury.

Objective: Neuropathic pain is a common complication after spinal cord injury (SCI). Transcranial direct current stimulation (tDCS) has been confirmed to be effective in relieving neuropathic pain in patients with SCI. The aim of this study is to investigate the effect of tDCS on neuropathic pain induced by SCI and its underlying mechanism. Materials and methods: The SCI model was induced by a clip-compression injury and tDCS stimulation was performed for two courses (5 days/each). The motor function was evaluated by Basso-Beattie-Bresnahan (BBB) score, and the thermal withdrawal threshold was evaluated by the thermal radiation method. The effects of tDCS on the cerebral cortex, thalamus, midbrain, and medulla were detected by the enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Results: The results showed that SCI reduced the thermal withdrawal threshold and increased the concentration of inflammatory cytokines in the cortex, thalamus, midbrain, and medulla, including the tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). In addition, the activation of microglia and the proportion of M1 phenotypic polarization increased significantly in the ventral posterolateral (VPL), ventral tegmental (VTA), and periaqueductal gray (PAG) regions after SCI. After tDCS treatment, the thermal withdrawal threshold and motor function of SCI rats were significantly improved compared to the vehicle group. Meanwhile, tDCS effectively reduced the concentration of pro-inflammatory cytokines in the cortex, thalamus, midbrain, and medulla and increased the concentration of anti-inflammatory cytokines interleukin-10 (IL-10) in the thalamus. In addition, tDCS reduced the proportion of the M1 phenotype of microglia in VPL, VTA, and PAG regions and increase the proportion of the M2 phenotype. Conclusion: The results suggest that tDCS can effectively relieve SCI-induced neuropathic pain. Its mechanism may be related to regulating the inflammatory and anti-inflammatory cytokines in corresponding brain regions via promoting the phenotypic transformation of microglia.

The prelimbic cortex regulates itch processing by controlling attentional bias.

Itch is a complex and unpleasant sensory experience. Recent studies have begun to investigate the neural mechanisms underlying the modulation of sensory and emotional components of itch in the brain. However, the key brain regions and neural mechanism involved in modulating the attentional processing of itch remain elusive. Here, we showed that the prelimbic cortex (PrL) is associated with itch processing and that the manipulation of itch-responsive neurons in the PrL significantly disrupted itch-induced scratching. Interestingly, we found that increasing attentional bias toward a distracting stimulus could disturb itch processing. We also demonstrated the existence of a population of attention-related neurons in the PrL that drive attentional bias to regulate itch processing. Importantly, itch-responsive neurons and attention-related neurons significantly overlapped in the PrL and were mutually interchangeable in the regulation of itch processing at the cellular activity level. Our results revealed that the PrL regulates itch processing by controlling attentional bias.

Ulinastatin inhibits microglia activation in spinal cord via P2Y12 receptor in a rat neuropathic pain model.

Ulinastatin, a broad spectrum of serine protease inhibitor, has been found to alleviate neuropathic pain (NPP). However, its mechanism is not completely clear. Here, a sciatic nerve ligation rat model and BV2 microglial cells were used to investigate the effect of Ulinastatin on the activation of microglia and P2Y12 receptors in vivo and in vitro. Levels of P2Y12 receptor and NF-κB (P65) expression in the dorsal horn of the lumbar enlargement region of the spinal cord and BV2 cells were assessed by immunohistochemistry and double-label immunofluorescence assays. Levels of IL-1ß and TNF-α in cell culture medium and cerebrospinal fluid (CSF) were examined by ELISA. The results showed that Ulinastatin reduced the release of inflammatory IL-1ß and TNF-α by inhibiting the activation of spinal microglia. Ulinastatin down-regulated P2Y12 receptor and NF-κB (P65) expression in the spinal microglia of the chronic constrictive injury model. The results indicated that Ulinastatin may attenuate the activation of spinal microglia after peripheral nerve injury by inhibiting the activation of P2Y12 receptor signal pathway in microglia. NF-kB may play a key role in the mechanism of Ulinastatin.

Corticostriatal Neurons in the Anterior Auditory Field Regulate Frequency Discrimination Behavior.

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

Transient hearing abnormalities precede social deficits in a mouse model of autism.

Hearing abnormalities are important symptoms of autism spectrum disorders (ASDs), a neurological and developmental disorder. However, the characteristics of hearing abnormalities associated with ASD during development have not been fully investigated. We found that in Shank3B knockout mice (a high-confidence mouse model of ASD), transient hearing abnormalities can be found in auditory brainstem response, auditory cortical activity, as well as acoustic startle response. More importantly, all hearing abnormalities at 4 weeks were most prominent and preceded the onset of social deficits at 6 weeks. These hearing abnormalities gradually recovered with age. In addition, analysis of ABR data at 4 weeks using Support Vector Machine (SVM) can faithfully predict the genotype of mice with an accuracy of 85.71%. These findings not only revealed hearing changes in Shank3B knockout autistic-like mice during development, but also suggested that hearing abnormalities could potentially be used as an early and effective indicator of ASD risk.

Enhancement in the water resistance and thermal stability of Na3HTiF8:Mn4+ by co-doping with organic amine cations.

Mn4+-doped fluoride red light phosphors are widely utilized in various fields, and their luminous performance is influenced by their stability in high humidity and temperature environments. By incorporating TEOAH+ (TEOAH+ = (HOCH2CH2)3NH+) into the Na2TiF6 matrix, Na3HTiF8:Mn4+,TEOAH+ with improved thermal stability and water resistance was synthesized. Enhancement in the luminescence thermal stability is supported by its strong negative thermal quenching (NTQ) effect, which is attributed to the phonon-induced mechanism wherein the probability of radiative transitions increases much faster than the probability of non-radiative transitions. Additionally, the integrated emission intensity of the optimal sample Na3HTiF8:Mn4+,0.15TEOAH+ was maintained at 70.1% after being immersed in water for 360 min, which may be attributed to the addition of TEOAH+ cations in the structure, thus increasing its structural rigidity. The prototype light-emitting diode (LED) has a narrow emission band, 88.6% color gamut, and 83.1 lm W-1 light efficiency, according to the National Television Standards Committee (NTSC). The qualities of the phosphor make it an ideal candidate for back-lighting devices.

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer's Disease.

Neurons, glial cells and blood vessels are collectively referred to as the neurovascular unit (NVU). In the Alzheimer's disease (AD) brain, the main components of the NVU undergo pathological changes. Transcranial direct current stimulation (tDCS) can protect neurons, induce changes in glial cells, regulate cerebral blood flow, and exert long-term neuroprotection. However, the mechanism by which tDCS improves NVU function is unclear. In this study, we explored the effect of tDCS on the NVU in mice with preclinical AD and the related mechanisms. 10 sessions of tDCS were given to six-month-old male APP/PS1 mice in the preclinical stage. The model group, sham stimulation group, and control group were made up of APP/PS1 mice and C57 mice of the same age. All mice were histologically evaluated two months after receiving tDCS. Protein content was measured using Western blotting and an enzyme-linked immunosorbent assay (ELISA). The link between glial cells and blood vessels was studied using immunofluorescence staining and lectin staining. The results showed that tDCS affected the metabolism of Aß; the levels of Aß, amyloid precursor protein (APP) and BACE1 were significantly reduced, and the levels of ADAM10 were significantly increased in the frontal cortex and hippocampus in the stimulation group. In the stimulation group, tDCS reduced the protein levels of Iba1 and GFAP and increased the protein levels of NeuN, LRP1 and PDGRFß. This suggests that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage. Increased blood vessel density and blood vessel length, decreased IgG extravasation, and increased the protein levels of occludin and coverage of astrocyte foot processes with blood vessels suggested that tDCS had a protective effect on the blood-brain barrier. Furthermore, the increased numbers of Vimentin, S100 expression and blood vessels (lectin-positive) around Aß indicated that the effect of tDCS was mediated by astrocytes and blood vessels. There was no significant difference in these parameters between the model group and the sham stimulation group. In conclusion, our results show that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage, providing further support for the use of tDCS as a treatment for AD.

Anodal transcranial direct current stimulation alleviates cognitive impairment in an APP/PS1 model of Alzheimer's disease in the preclinical stage.

Anodal transcranial direct current stimulation (AtDCS) has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer's disease in the preclinical stage. However, this enhancement was only observed immediately after AtDCS, and the long-term effect of AtDCS remains unknown. In this study, we treated 26-week-old mouse models of Alzheimer's disease in the preclinical stage with 10 AtDCS sessions or sham stimulation. The Morris water maze, novel object recognition task, and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice. Western blotting was used to detect the relevant protein content. Morphological changes were observed using immunohistochemistry and immunofluorescence staining. Six weeks after treatment, the mice subjected to AtDCS sessions had a shorter escape latency, a shorter path length, more platform area crossings, and spent more time in the target quadrant than sham-stimulated mice. The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice. Furthermore, AtDCS reduced the levels of amyloid-ß42 and glial fibrillary acidic protein, a marker of astrocyte activation, and increased the level of neuronal marker NeuN in hippocampal tissue. These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer's disease in the preclinical stage, with improvements that last for at least 6 weeks.

Benefits in Alzheimer's Disease of Sensory and Multisensory Stimulation.

Alzheimer's disease (AD) is a serious neurodegenerative disease, which seriously affects the behavior, cognition, and memory of patients. Studies have shown that sensory stimulation can effectively improve the cognition and memory of AD patients, and its role in brain plasticity and neural regulation is initially revealed. This paper aims to review the effect of various sensory stimulation and multisensory stimulation for AD, and to explain the possible mechanism, so as to provide some new ideas for further research in this field. We searched the Web of Science and PubMed databases (from 2000 to October 27, 2020) for literature on the treatment of AD with sensory and multisensory stimulation, including music therapy, aromatherapy, rhythmic (e.g., visual or acoustic) stimulation, light therapy, multisensory stimulation, and virtual reality assisted therapy, then conducted a systematic analysis. Results show these sensory and multisensory stimulations can effectively ameliorate the pathology of AD, arouse memory, and improve cognition and behaviors. What's more, it can cause brain nerve oscillation, enhance brain plasticity, and regulate regional cerebral blood flow. Sensory and multisensory stimulation are very promising therapeutic methods, and they play an important role in the improvement and treatment of AD, but their potential mechanism and stimulation parameters need to be explored and improved.

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aß42 Burden at the Early Stage of Alzheimer's Disease in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease. Intervention in the early stage of AD is a new path for AD treatment that is being explored. The behavioral and pathological effects of anodal transcranial direct current stimulation (AtDCS) at the early stage of AD in the mouse model, amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, were investigated based on our previous studies. Thirty-three 6-month-old male APP/PS1 mice were randomly divided into the model group (AD group), model + sham stimulation group (ADST group) and stimulation group (ADT group). Eleven 6-month-old male C57 wild-type mice were randomly selected as a control group (CTL group). The ADT group received 10 AtDCS sessions. The Morris water maze (MWM) task and novel object recognition (NOR) task were used to test mouse memory. Nissl staining, Western blot (WB), immunohistochemistry and immunofluorescence staining of ß-amyloid (Aß42), glial fibrillary acidic protein (GFAP) and NF200 were conducted for pathological analysis. The ADT group and the CTL group had a shorter escape latency and more platform-region crossings than the AD group and ADST group in the MWM. There was no significant difference in the discrimination index among the groups in the NOR task. Pathological analysis showed visible differences between the AD group and ADT group. This study revealed that early-stage APP/PS1 transgenic mice did not show recognition memory impairment. AtDCS effectively improved spatial learning and memory in the early-stage APP/PS1 transgenic mouse model of AD, alleviating Aß burden and having a protective effect on neurons. AtDCS could improve AD-related symptoms by activating many glial cells to promote the degradation and clearance of Aß or directly affecting production and degradation of Aß to reduce glial activation. AtDCS is an effective means of early intervention in the early stage of AD.

The projections from the anterior cingulate cortex to the nucleus accumbens and ventral tegmental area contribute to neuropathic pain-evoked aversion in rats.

Although the anterior cingulate cortex (ACC) plays a vital role in neuropathic pain-related aversion, the underlying mechanisms haven't been fully studied. The mesolimbic dopamine system encodes reward and aversion, and participates in the exacerbation of chronic pain. Therefore, we investigated whether the ACC modulates aversion to neuropathic pain via control of the mesolimbic dopamine system, in a rat model of chronic constriction injury (CCI) to the sciatic nerve. Using anterograde and retrograde tracings, we confirmed that a subgroup of ACC neurons projected to the nucleus accumbens (NAc) and ventral tegmental area (VTA), which are two crucial nodes of the mesolimbic dopamine system. Combining electrophysiology in juvenile rats 7 days post-CCI, we found that the NAc/VTA-projecting neurons were hyperexcitable after CCI. Chemogenetic inhibition of these projections induced conditioned place preference in young adult rats 10-14 days post-CCI, without modulating the evoked pain threshold, whereas activation of these projections in sham rats mimicked aversive behavior. Furthermore, the function of the ACC projections was probably mediated by NAc D2-type medium spiny neurons and VTA GABAergic neurons. Taken together, our findings suggest that projections from the ACC to the NAc and VTA mediate neuropathic pain-related aversive behavior.

Colorimetric determination of ascorbic acid based on carbon quantum dots as peroxidase mimetic enzyme.

Carbon quantum dots (CQDs) were synthesized from litchi peel, exhibiting a peroxidase-like activity and enabling the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in association with H2O2 to generate blue oxidized TMB (ox-TMB) with a strong absorption peak at 652 nm. Interestingly, the ox-TMB could be further reduced by ascorbic acid (AA) leading to fading of the blue color and an absorbance decrease. Thus, a convenient and sensitive colorimetric method for detection of AA using CQDs as peroxidase mimics was established. Several factors, such as acidity, temperature, incubating time, and TMB concentration, which might influence the response of the analysis signal, were optimized. The results showed that the decrease of absorbance (ΔA) was in good linear agreement with AA concentration in the range of 1.0-105 µM, with a low detection limit of 0.14 µM. The feasibility of this method was also investigated in commercial beverages with the 94.3-110.0% recovery.

After-effects of repetitive anodal transcranial direct current stimulation on learning and memory in a rat model of Alzheimer's disease.

Repetitive anodal transcranial direct current stimulation (tDCS) in a rat model of Alzheimer's disease (AD) has been shown to have distinct neuroprotective effects. Moreover, the effects of anodal tDCS not only occur during the stimulation but also persist after the stimulation has ended (after-effects). Here, the duration of the after-effects induced by repetitive anodal tDCS was investigated based on our previous studies. Adult male Sprague-Dawley rats were divided into three groups: a sham group, a ß-amyloid (Aß) group (AD group) and a stimulation group (ATD group). Aß was injected into the bilateral hippocampi of the rats in the AD and ATD groups to produce the AD model. Rats in the ATD group underwent 10 sessions of anodal tDCS, and the after-effects of repetitive anodal tDCS were evaluated by behavioral and histological analyses. A Morris water maze (MWM) was utilized on a monthly basis to assess spatial learning and memory abilities. The ATD group showed shorter escape latencies and more platform region crossings than the AD group. Hippocampal choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) immunohistochemical analyses were carried out after the last MWM assessment. The immunohistochemistry results showed notable differences among the groups, particularly between the AD and ATD groups. This study reveals that repetitive anodal tDCS can not only improve cognitive function and memory performance but also has long-term after-effects that persist for 2 months.

Anterior Auditory Field Is Needed for Sound Categorization in Fear Conditioning Task of Adult Rat.

Both primary auditory cortex (A1) and anterior auditory field (AAF) are core regions of auditory cortex of many mammalians. While the function of A1 has been well documented, the role of AAF in sound related behavioral remain largely unclear. Here in adult rats, sound cued fear conditioning paradigm, surgical ablation, and chemogenetic manipulations were used to examine the role of AAF in fear related sound context recognition. Precise surgical ablation of AAF cannot block sound cued freezing behavior but the fear conditioning became non-selective to acoustic cue. Reversible inhibition of AAF using chemogenetic activation at either training or testing phase can both lead to strong yet non-selective sound cued freezing behavior. These simple yet clear results suggested that in sound cued fear conditioning, sound cue and detailed content in the cue (e.g., frequency) are processed through distinct neural circuits and AAF is a critical part in the cortex dependent pathway. In addition, AAF is needed and playing a gating role for precise recognition of sound content in fear conditioning task through inhibiting fear to harmless cues.

Ulinastatin attenuates neuropathic pain via the ATP/P2Y2 receptor pathway in rat models.

Ulinastatin, a serine protease inhibitor, which has anti-inflammatory properties and neuroprotective effects, is used to treat acute inflammatory disorders. Recent evidence indicates that administration of ulinastatin alleviates pain in rat model of neuropathic pain (NPP). However, its effect on NPP and the underlying mechanism requires further study. In this study, we evaluated the role of intrathecal administration of ulinastatin in rats with sciatic nerve ligation and observed the effect of ulinastatin on the ATP/P2Y2 receptor pathway. We performed mechanical and thermal sensitivity measurements, immunohistochemistry and double-label immunofluoresence studies to evaluate P2Y2 receptor and adenosine 5'-monophosphate-activated protein kinase (AMPK) expression in the dorsal horn of the lumbar enlargement region of the spinal cord, and a luciferase assay for the detection of ATP levels in the cerebrospinal fluid. The results showed that ulinastatin prevented the development of mechanical allodynia and thermal hypersensitivity in the rat sciatic nerve ligation model. Ulinastatin reduced the level of extracellular ATP, down-regulated P2Y2 receptor and AMPK expression in the spinal dorsal horn of the chronic constrictive injury model. We found that increased expression of P2Y2 receptor in microglia was likely involved in the activation of microglia after nerve injury, and ulinastatin inhibited the abnormal microglia activation in the dorsal horn after nerve injury. These findings demonstrated that ulinastatin might be a potential and effective drug for the treatment of NPP via the suppression of the ATP/P2Y2 receptor pathway.

Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats.

Background: Transcranial direct current stimulation (tDCS) is widely used to treat human nerve disorders and neuropathic pain by modulating the excitability of cortex. The effectiveness of tDCS is influenced by its stimulation parameters, but there have been no systematic studies to help guide the selection of different parameters. Objective: This study aims to assess the effects of tDCS of primary motor cortex (M1) on chronic neuropathic pain in rats and to test for the optimal parameter combinations for analgesia. Methods: Using the chronic neuropathic pain models of chronic constriction injury (CCI), we measured pain thresholds before and after anodal-tDCS (A-tDCS) using different parameter conditions, including stimulation intensity, stimulation time, intervention time and electrode located (ipsilateral or contralateral M1 of the ligated paw on male/female CCI models). Results: Following the application of A-tDCS over M1, we observed that the antinociceptive effects were depended on different parameters. First, we found that repetitive A-tDCS had a longer analgesic effect than single stimulus, and both ipsilateral-tDCS (ip-tDCS) and contralateral-tDCS (con-tDCS) produce a long-lasting analgesic effect on neuropathic pain. Second, the antinociceptive effects were intensity-dependent and time-dependent, high intensities worked better than low intensities and long stimulus durations worked better than short stimulus durations. Third, timing of the intervention after injury affected the stimulation outcome, early use of tDCS was an effective method to prevent the development of pain, and more frequent intervention induced more analgesia in CCI rats, finally, similar antinociceptive effects of con- and ip-tDCS were observed in both sexes of CCI rats. Conclusion: Optimized protocols of tDCS for treating antinociceptive effects were developed. These findings should be taken into consideration when using tDCS to produce analgesic effects in clinical applications.