Immersive virtual reality-based rehabilitation for subacute stroke: a randomized controlled trial.

OBJECTIVE: Few effective treatments improve upper extremity (UE) function after stroke. Immersive virtual reality (imVR) is a novel and promising strategy for stroke UE recovery. We assessed the extent to which imVR-based UE rehabilitation can augment conventional treatment and explored changes in brain functional connectivity (FC) that were related to the rehabilitation. METHODS: An assessor-blinded, parallel-group randomized controlled trial was performed with 40 subjects randomly assigned to either imVR or Control group (1:1 allocation), each receiving rehabilitation 5 times per week for 3 weeks. Subjects in the imVR received both imVR and conventional rehabilitation, while those in the Control received conventional rehabilitation only. Our primary and secondary outcomes were the Fugl-Meyer assessment's upper extremity subscale (FMA-UE) and the Barthel Index (BI), respectively. Both intention-to-treat (ITT) and per-protocol (PP) analyses were performed to assess the effectiveness of the trial. For both the FMA-UE/BI, a one-way analysis of covariance (ANCOVA) model was used, with the FMA-UE/BI at post-intervention or at follow-up, respectively, as the dependent variable, the two groups as the independent variable, baseline FMA-UE/BI, age, sex, site, time since onset, hypertension and diabetes as covariates. RESULTS: Both ITT and PP analyses demonstrated the effectiveness of imVR-based rehabilitation. The FMA-UE score was greater in the imVR compared with the Control at the post-intervention (mean difference: 9.1 (95% CI 1.6, 16.6); P = 0.019) and follow-up (mean difference:11.5 (95% CI 1.9, 21.0); P = 0.020). The results were consistent for BI scores. Moreover, brain FC analysis found that the motor function improvements were associated with a change in degree in ipsilesional premotor cortex and ipsilesional dorsolateral prefrontal cortex immediately following the intervention and in ipsilesional visual region and ipsilesional middle frontal gyrus after the 12-week follow-up. CONCLUSIONS: ImVR-based rehabilitation is an effective tool that can improve the recovery of UE functional capabilities of subacute stroke patients when added to standard care. These improvements were associated with distinctive brain changes at two post-stroke timepoints. The study results will benefit future patients with stroke and provide evidence for a promising new method of stroke rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03086889.

Neuroanatomical restoration of salience network links reduced headache impact to cognitive function improvement in mild traumatic brain injury with posttraumatic headache.

BACKGROUND: Neuroanatomical alterations have been associated with cognitive deficits in mild traumatic brain injury (MTBI). However, most studies have focused on the abnormal gray matter volume in widespread brain regions using a cross-sectional design in MTBI. This study investigated the neuroanatomical restoration of key regions in salience network and the outcomes in MTBI. METHODS: Thirty-six MTBI patients with posttraumatic headache (PTH) and 34 matched healthy controls were enrolled in this study. All participants underwent magnetic resonance imaging scans and were assessed with clinical measures during the acute and subacute phases. Surface-based morphometry was conducted to get cortical thickness (CT) and cortical surface area (CSA) of neuroanatomical regions which were defined by the Desikan atlas. Then mixed analysis of variance models were performed to examine CT and CSA restoration in patients from acute to subacute phase related to controls. Finally, mediation effects models were built to explore the relationships between neuroanatomical restoration and symptomatic improvement in patients. RESULTS: MTBI patients with PTH showed reduced headache impact and improved cognitive function from the acute to subacute phase. Moreover, patients experienced restoration of CT of the left caudal anterior cingulate cortex (ACC) and left insula and cortical surface area of the right superior frontal gyrus from acute to subacute phase. Further mediation analysis found that CT restoration of the ACC and insula mediated the relationship between reduced headache impact and improved cognitive function in patients. CONCLUSIONS: These results showed that neuroanatomical restoration of key regions in salience network correlated reduced headache impact with cognitive function improvement in MTBI with PTH, which further substantiated the vital role of salience network and provided an alternative clinical target for cognitive improvement in MTBI patients with PTH.

Sequential neural activity in sensorimotor area and mirror neural system for graded mirror therapy with imagined hand movements.

BACKGROUND: Graded motor imagery (GMI) therapy is a neural rehabilitative physiotherapy that has been shown to alleviate the severity of complex regional pain syndrome, phantom limb pain and disability. OBJECTIVE: To identify neural networks associated with the use of graded mirror therapy (MT) while imagining hand movements. METHODS: We made a block-design functional magnetic resonance imaging study of MT included three experiments: (1) immobile unimanual MT (IU-MT), in which the right hand flexed and made a fist, which then remained immobile; (2) mobilization unimanual MT (MU-MT), in which the right hand performed a flexion-extension movement; and (3) mobilization bimanual MT (MB-MT), in which both hands performed a flexion-extension movement. When subjects started their hand movements, they gazed at the mirror and imagined the same movement behind the mirror. RESULTS: We discovered that the sensorimotor area of the left brain, superior temporal gyrus/middle temporal gyrus (STG/MTG) of the right brain and visual areas were activated by IU-MT. In MU-MT, only the STG/MTG was activated. Furthermore, MB-UT mostly activated the sensorimotor area and STG of the right brain. However, there were no brain areas activated by MU-MT compared with IU-MT or MB-MT; but, MB-MT activated more motor areas than IU-MT. Importantly, we determined that the level of mirror imagery was negatively correlated with signals in the mirror neuron system (MNS) and positively related with the signals in the sensorimotor areas. CONCLUSIONS: We suggest that graded MT might be a sequential therapeutic program that can enhance the sensorimotor cortex. The MNS might have an initiating role in graded MT. Thus, there is the possibility that graded MT is a helpful treatment strategy for the rehabilitation of dysfunctional patients.

Effect of electro-acupuncture on the BDNF-TrkB pathway in the spinal cord of CCI rats.

Microglia, which comprise a sensor for pathological events in the central nervous system, may be triggered by nerve injury and transformed from a quiescent state into an activated state; ionised calcium binding adaptor molecule 1 (Iba1) is a sensitive marker associated with activated microglia. Accumulated evidence suggests that spinal activated microglia and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signalling pathway play major roles in the production and development of neuropathic pain. Electro-acupuncture (EA) has a positive effect on relieving chronic neuropathic pain; however, the underlying mechanisms remain unclear. To determine the significance of EA in the treatment of neuropathic pain mediated by activated microglia and the BDNF-TrkB signalling pathway in the spinal cord, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values were recorded to assess hyperalgesia and allodynia. In addition, the amount of activated microglia and BDNF were assessed via immunofluorescence. Iba1, BDNF and TrkB mRNA expression levels were examined using qPCR; the protein levels of BDNF, p-TrkB and TrkB in the spinal cord were analysed via western blotting. The present study demonstrated that EA treatment increased the MWT and TWL values. EA significantly inhibited the proportion of activated microglia and BDNF expression in the spinal cord after chronic constrictive injury (CCI). Furthermore, EA decreased the expression of BDNF and TrkB at both the mRNA and protein levels in the spinal cord of CCI rats. These findings suggest that the analgesic effect of EA may be achieved by inhibiting the activation of spinal microglia and subsequently blocking the BDNF-TrkB signalling pathway.

[Effects of electroacupuncture on activation of microglia cells in spinal cord in rats with neuropathic pain].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the activation of microglia cells in the L4 to L6 spinal cord in rats with neuropathic pain, so as to investigate whether EA could inhibit the activation of spinal microglial cells and regulate the expression of brain-derived neurotrophic factor (BDNF) to achieve the analgesic effect. METHODS: Forty male Sprague Dawley rats were randomly divided into a normal group, a sham-model group, a model group and an EA group, 10 rats in each one. The rats in the normal group received no treatment; the rats in sham-model group were treated with operation to exposure sciatic nerve for 2 to 3 min (no knot); the rats in the remaining groups were treated with model establishment of chronic constrictive injury (CCI). 7 days after model establishment, the rats in the EA group were treated with EA at "Zusanli" (ST 36) and "Yanglingquan" (GB 34), 30 min per time, once a day for consecutive 7 days. Only immobilization was used in the remaining groups the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of affected side feet were respectively measured before model establishment and 3 days, 5 days, 7 days, 10 days, 12 days and 14 days after model establishment; 14 days after model establishment, rats were sacrificed; the immunohistochemical method was used to measure the expression of Iba1 and BDNF in the sample of L4 to L6 spinal cord; real-time fluorescent quantitative PCR was used to measure the expression BDNF mRNA. RESULTS: Compared with the sham-model group, the pain threshold was decreased significantly in the model group (P<0.05), leading to hyperpathia. After EA treatment, compared with the model group, the pain threshold was increased significantly in the EA group (P<0.05). 14 days after operation, the microglia cells in the L4 to L6 spinal cord, expression of BDNF and level of mRNA in the model group were significantly higher than those in the normal group and sham-model group (all P<0.01); those in the EA group were significantly lower than those in the model group (all P<0.01). CONCLUSIONS: The analgesic effect on neuropathic pain is likely to be achieved by EA through inhibiting the activation of spinal microglia cells and down-regulating the expression of BDNF.

Electro-acupuncture at Governor Vessel improves neurological function in rats with spinal cord injury.

OBJECTIVE: To determine the effects of electro-acupuncture (EA) at Governor Vessel (GV) on the locomotor function in spinal cord injury (SCI) rats and explore the underlying mechanism. METHODS: Thirtytwo male Sprague-Dawley rats were randomly divided into four groups namely: the sham group (with sham operation); the untreated group (without treatment after spinal cord impact); the EA-1 group [EA applied at Baihui (GV 20) and Fengfu (GV 16) after spinal cord impact] and the EA-2 group [with EA applied at Dazhui (GV 14) and Mingmen (GV 4) after spinal cord impact]. Real-time quantitative-polymerase chain reaction (RT-PCR) and Western Blotting were used to assess changes in the mRNA and protein expression levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) at 7 weeks following EA administration. In addition, the Basso-Beattie-Bresnahan (BBB) Locomotor Rating Scale was assessed at 1 day, 1 week, 3 weeks and 7 weeks post-injury. RESULTS: The results showed that EA stimulation induced neuroprotective effects after SCI correlated with the up-regulation of BDNF and NT-3 (P<0.05). Furthermore, EA stimulation at GV 14 and GV 4 could significantly promote the recovery of locomotor function and this may be linked to the up-regulation of BDNF and NT-3 (P<0.05). CONCLUSIONS: EA treatment applied at GV acupoints either within the injury site or adjacent undamaged regions near the brain can improve functional recovery, which may be correlated with the upregulation of BDNF and NT-3. In addition, it would be more effective to administer EA at GV 14 and GV 4 near the injury site of the SCI rats.

[Moderate and severe persistent allergic rhinitis treated with acupoint application therapy of the different intensity: a randomized controlled trial].

OBJECTIVE: To evaluate the clinical therapeutic effects and safety on moderate and severe persistent allergic rhinitis treated with acupoint application therapy of the different intensity during the dog days. METHODS: One hundred and sixty patients of moderate and severe persistent allergic rhinitis were randomized into a No.1 treatment group, a No.2 treatment group, a No.3 treatment group and a placebo group, 40 cases in each one. The same acupoints were used in the four groups, named Dazhui (GV 14), Dingchuan (EX-B1), Feishu (BL 13), Pishu (BL 20), Mingmen (GV 4), Gaohuang (BL 43), Shenshu (BL 23) and Qihai (CV 6). In the three treatment groups, the fine powder of the ingredients (semen brassicae, radix angeliceae, asarum sieboldii, rhizome corydalis) of compound baijiezi formula was used. In the No.1 treatment group, the herbal paste (ginger-prepared paste) was prepared with ginger juice and the above herbal powder. In the No.2 and No.3 treatment groups, the herbal paste (honey-prepared paste) was prepared with honey with the above herbal powder. In the placebo group, the pseudo-herbal paste of the same appearance was prepared with millet powder and distilled water. The acupoint application was given for 2 h in the No.1 and No.2 groups and was for 6 h in the No.3 treatment group and the placebo group. The acupoint application therapy was given once every week during the dogdays, continuously for 5 weeks. The total nasal symptom score (TNSS), the score of the rhinoconjunctivitis quality of life questionnaire (RQLQ) and the count of blood eosinophils (EOS) were observed in the patients of the 4 groups before and after treatment. The clinical therapeutic effects were compared among the 4 groups. The incidences of the skin adverse reactions were observed in each treatment group. RESULTS: After treatment, the scores of TNSS and RQLQ were all reduced as compared with those before treatment in the three treatment groups (P<0.05, P<0.01), in which, the improvements in the No.3 treatment group were better than those in the No.1 treatment group and the No.2 treatment group (both P<0.05). After treatment, the count of EOS was all reduced as compared with that before treatment in the three treatment groups (all P<0.05). The differences were not significant statistically among the three treatment groups (all P>0.05). The total effective rate was 85.0% (34/40) in the No.3 treatment group, better than 76.3% (29/38) in the No.1 treatment group, 71.8% (28/39) in the No.2 treatment group and 5.0% (2/40) in the placebo group (P<0.05, P<0.01). The incidences of the skin adverse reaction in the No.3 treatment group and the No.2 treatment group were lower than those in the No.1 treatment group (both P<0.01). CONCLUSION: The acupoint application of the different intensity relieves the symptoms and improves the living quality in the patients of moderate and severe persistent allergic rhinitis. The stimulation of the ginger-prepared herbal paste is strong and induces skin blisters after 2 h herbal application. The stimulation of the honey-prepared herbal paste is moderate and does not induce blisters. The 6 h stimulation of the honey-prepared herbal paste is mild and the therapeutic effect is optimal.