Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory and debilitating disease that involves the systemic imbalance of the immune network. Previous studies have shown that acupuncture can help treat RA. However, its specific mechanisms are not fully understood. Thus, the present study was designed to clarify the mechanisms of acupuncture acted on RA via immune network modulation using complete Freund's adjuvant (CFA)-induced arthritic rats. Results revealed that manual acupuncture (MA) could alleviate the inflammation and pain of infected joints. Moreover, MA could effectively stimulate the innate immune cytokines (IL-1[Formula: see text], IL-1[Formula: see text], IL-6, IL-7, IL-18, TNF-[Formula: see text]) and adaptive immunity cytokines (IL-2, IL-12, IFN-[Formula: see text], IL-4, IL-5, IL-10, IL-13, IL-17) as the main part of the immune response and repaired damage of RA. These complex immunomodulatory processes were analyzed quantitatively by cell-cell communication (CCC) networks. The CCC networks demonstrated that the immune networks were enhanced with the development of RA, while MA enhanced the immune networks in the early stage to act on RA and promoted the immune-network to a normal level at the late stage. Moreover, we found that monocyte/macrophage and endothelial cells were the key cells of innate immunity and body cells; T1, T2 and B cells were the key cells of adaptive immunity, which were also the main target cells for MA regulation.

Objectives: To investigate the effect of multi-session transcranial direct current stimulation (tDCS) over the prefrontal area, left dorsolateral prefrontal cortex (DLPFC), and bilateral fronto-temporo-parietal cortices (FTPCs) in patients with prolonged disorders of consciousness (DOC) and to examine the altered cortical interconnections using non-linear electroencephalography (EEG).Methods: In this open-label controlled study, conventional treatments were implemented in both the control and tDCS groups, together with 80 tDCS sessions only in the tDCS group. The order of tDCS targets was as follows: prefrontal area, left FTPC, right FTPC, and left DLPFC. The Coma Recovery Scale-Revised (CRS-R) and non-linear EEG index were evaluated before and after the treatment. Additionally, the modified Glasgow Outcome Scale (mGOS) was used as a follow-up evaluation at 12 months after the disease onset.Results: The CRS-R improved significantly in both groups after the treatment. However, the CRS-R and mGOS were more significantly improved in the tDCS group than in the control group. Among the cross approximate entropy (C-ApEn) indices, the local CA-PA and CA-FA under the affected painful stimulus condition and all local and remote indices of the unaffected side under the unaffected painful stimulus condition were significantly higher in the tDCS group than in the control group. Multivariate logistic regression analysis revealed that group and type were the main relevant factors based on mGOS improvement. Multivariate linear regression analysis revealed that group, CA-FA, and CU-MTU were the main relevant factors based on CRS-R improvement under the affected painful stimulus conditions, whereas only CU-MTU and CU-FPU were relevant under the unaffected painful stimulus condition.Conclusion: Multi-target and multi-session tDCS could improve the cortical connections between the primary sensorimotor and frontal cortices of the affected hemisphere and the prefrontal-parietal and temporo-parietal associative cortical networks of the unaffected hemisphere. Thus, this tDCS protocol may be used as an add-on treatment for prolonged DOC.

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The induction of a coma by traumatic brain injury (TBI) is a crucial factor for poor clinical prognoses. We report that acupuncture at the hand 12 Jing-Well points (HTWP) improved consciousness and neurologic function in TBI rats. Gene chip analyses showed that HTWP acupuncture mostly activated genes modulating neuronal projections (P2rx7, P2rx3, Trpv1, Tacr1, and Cacna1d), protein secretion (Exoc1, Exoc3l1, Fgb, and Fgr), and dopamine (DA) receptor D3 (Drd3) in the ventral periaqueductal gray (vPAG), among which the expression rate of P2rx7 was the most obviously increased. Acupuncture also increased the expression and excitability of DA and P2RX7 neurons, and the DA neurons expressed P2RX7, P2RX3, and TRPV1 in the vPAG. Intracerebroventricular administration of P2RX7, P2RX3, or TRPV1 antagonists blocked acupuncture-induced consciousness, and the subsequent injection of a P2RX7 antagonist into the vPAG nucleus also inhibited this effect. Our findings provide evidence that acupuncture alleviates TBI-induced comas via DA neurons expressing P2RX7 in the vPAG, so as to reveal the cellular and molecular mechanisms of the improvement of TBI clinical outcomes by HTWP acupuncture.

Objectives: Acupuncture has been found to be effective at relieving many inflammatory pain conditions, including rheumatoid arthritis (RA). We aimed to assess the anti-inflammatory potential of manual acupuncture (MA) treatment of RA using adjuvant-induced arthritic (AIA) rats and to explore the underlying mechanisms. Methods: The anti-inflammatory and analgesic actions of MA at ST36 ( Zusanli) in AIA rats were assessed using paw withdrawal latency and swelling, histological examination and cytokine detection by enzyme-linked immunoassay (ELISA). The cell–cell communication (CCC) network was analyzed with a multiplex immunoassay of 24 immune factors expressed in the inflamed joints, and the macrophage and Treg populations and associated cytokines regulated by MA were investigated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR), ELISA and flow cytometry. Results: MA markedly decreased heat hyperalgesia and paw swelling in AIA rats. MA-treated rats also exhibited decreased levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β) coupled with increased anti-inflammatory cytokines (IL-10, transforming growth factor (TGF)-β1) in the ankle joints at protein and mRNA levels. CCC network analysis confirmed that macrophages are of critical importance and are potential therapeutic targets in RA. Repeated treatment with MA triggered a macrophage phenotypic switch in the paws, with fewer M1 macrophages. Prominent increases in the Treg cell population and TGF-β1 in the popliteal lymph nodes demonstrated the immunomodulatory effects of MA. Furthermore, a selective TGF-β1-receptor inhibitor, SB431542, attenuated the anti-inflammatory effects of MA and MA-induced suppression of the levels of M1-released cytokines. Conclusion: These findings provide novel evidence that the anti-inflammatory and analgesic effects of MA on RA act through phenotypic modulation involving the inhibition of M1 macrophage polarization and an increase in the Treg cell population, highlighting the potential therapeutic advantages of acupuncture in controlling pain and ameliorating inflammatory conditions.

Objectives: This study aimed to investigate the role of non-linear dynamic analysis (NDA) of the electroencephalogram (EEG) in predicting patient outcome in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS).Methods: This was a prospective longitudinal cohort study. A total of 98 and 64 UWS and MCS cases, respectively, were assessed. During admission, EEGs were acquired under eyes-closed and pain stimulation conditions. EEG nonlinear indices, including approximate entropy (ApEn) and cross-ApEn, were calculated. The modified Glasgow Outcome Scale (mGOS) was employed to assess functional prognosis 1 year following brain injury.Results: The mGOS scores were improved in 25 (26%) patients with UWS and 42 (66%) with MCS. Under the painful stimulation condition, both non-linear indices were lower in patients with UWS than in those with MCS. The frontal region, periphery of the primary sensory area (S1), and forebrain structure might be the key points modulating disorders of consciousness. The affected local cortical networks connected to S1 and unaffected distant cortical networks connecting S1 to the prefrontal area played important roles in mGOS score improvement.Conclusions: NDA provides an objective assessment of cortical excitability and interconnections of residual cortical functional islands. The impaired interconnection of the residual cortical functional island meant a poorer prognosis. The activation in the affected periphery of the S1 and the increase in the interconnection of affected local cortical areas around the S1 and unaffected S1 to the prefrontal and temporal areas meant a relatively favorable prognosis.

Objectives: Many post-traumatic patients with minimally conscious state are complicated by psychomotor inhibition state (PIS), which impedes further rehabilitation. The treatment of PIS is not satisfactory. This pilot study aimed to investigate effects of anodal transcranial direct current stimulation (A-tDCS) on PIS in post-traumatic patients and examine the altered cortical activation after tDCS using non-linear electroencephalogram (EEG). Methods:The study included 10 patients with post-traumatic PIS. An A-B design was used. The patients received 4 weeks of sham tDCS during Phase A, and they received A-tDCS over the prefrontal area and left dorsolateral prefrontal cortex (DLPFC) for 4 weeks (40 sessions) during Phase B. Conventional treatments were administered throughout both phases. JFK Coma Recovery Scale-Revised (CRS-R), apathy evaluation scale (AES), and the EEG non-linear indices of approximate entropy (ApEn) and cross approximate entropy (C-ApEn) were measured before Phase A, before Phase B, and after Phase B.Results: After A-tDCS treatment, CRS-R and AES were improved significantly. ApEn and C-ApEn results showed that the local cortical connection of bilateral sensorimotor areas with their peripheral areas could be activated by affected painful stimuli, while bilateral cerebral hemispheres could be activated by the unaffected painfulstimuli condition. Linear regression analysis revealed that the affected sensorimotor cortex excitability and unaffected local and distant cortical networks connecting the sensorimotor area to the prefrontal area play a major role in AES improvement. Conclusion:A-tDCS over the prefrontal area and left DLPFC improves PIS. The recovery might be related to increased excitability in local and distant cortical networks connecting the sensorimotor area to the prefrontal area. Thus, tDCS may be an alternative treatment for post-traumatic PIS.

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