LANCL1 as the Key Immune Marker in Neuropathic Pain.

Objective: This study is to explore key immune markers and changes of immune microenvironment in neuropathic pain (NeuP). Method: The data sets of GSE145199 and GSE145226 in Gene Expression Omnibus (GEO) database was used to analyze, and the key immune markers were verified by GSE70006 and GSE91396, and the infiltration degree of immune cells in different samples were analyzed by CIBERSORT analysis package. Results: In this study, we found a key immune marker, namely, LANCL1. Regulatory axis closely related to LANCL1 has also been found, namely, miR-6325/LANCL1 axis. In the immune infiltration analysis, we also found that the LANCL1 is positively correlated with T cells CD4 naïve (r = 0.880, p < 0.05). Conclusion: In this study, we found that LANCL1 may be a protective factor for NeuP, and the miR-6325/LANCL1 axis may be involved in the occurrence and development of NeuP. Cascade reactions including mast cells, macrophages, and T cells may be an important reason for the aggravation of nerve damage.

Regional homogeneity of intrinsic brain activity correlates with auditory-motor processing of vocal pitch errors.

It has been well documented that speakers produce rapid compensatory vocal adjustments for errors they perceive in their auditory feedback. The fact that they differ greatly in the degree to which they compensate for perceived errors, however, has received much less attention. The present study investigated whether intrinsic brain activity during resting can predict an individual's behavioral and cortical responses in compensating for pitch-shifted auditory feedback during vocalization. This relationship was investigated by correlating the regional homogeneity (ReHo) of resting-state fMRI signals with the vocal compensation and event-related potentials (N1 and P2) in response to pitch shifts of -200 and -500 cents. Behaviorally, the magnitudes of vocal compensation were significantly correlated with the ReHo values in the right supplementary motor area (SMA) for both -200 and -500 cents, the right primary motor cortex (M1) for -200 cents, and the left premotor cortex (PMC) for -500 cents. For both pitch shift sizes, there were significant correlations between ReHo and N1 amplitude in the left inferior frontal gyrus (IFG), right superior temporal gyrus (STG), bilateral M1, and left SMA. Significant correlations between ReHo and P2 amplitude were observed in the bilateral IFG, right STG, left SMA and M1 for -200 and -500 cents, the left PMC for -200 cents, and the right SMA for -500 cents. These findings provide the first evidence that regional homogeneity of intrinsic brain activity can predict behavioral and cortical responses in compensating for pitch errors in voice auditory feedback.

The impact of parkinson's disease on the cortical mechanisms that support auditory-motor integration for voice control.

Several studies have shown sensorimotor deficits in speech processing in individuals with idiopathic Parkinson's disease (PD). The underlying neural mechanisms, however, remain poorly understood. In the present event-related potential (ERP) study, 18 individuals with PD and 18 healthy controls were exposed to frequency-altered feedback (FAF) while producing a sustained vowel and listening to the playback of their own voice. Behavioral results revealed that individuals with PD produced significantly larger vocal compensation for pitch feedback errors than healthy controls, and exhibited a significant positive correlation between the magnitude of their vocal responses and the variability of their unaltered vocal pitch. At the cortical level, larger P2 responses were observed for individuals with PD compared with healthy controls during active vocalization due to left-lateralized enhanced activity in the superior and inferior frontal gyrus, premotor cortex, inferior parietal lobule, and superior temporal gyrus. These two groups did not differ, however, when they passively listened to the playback of their own voice. Individuals with PD also exhibited larger P2 responses during active vocalization when compared with passive listening due to enhanced activity in the inferior frontal gyrus, precental gyrus, postcentral gyrus, and middle temporal gyrus. This enhancement effect, however, was not observed for healthy controls. These findings provide neural evidence for the abnormal auditory-vocal integration for voice control in individuals with PD, which may be caused by their deficits in the detection and correction of errors in voice auditory feedback. Hum Brain Mapp 37:4248-4261, 2016. © 2016 Wiley Periodicals, Inc.

An interpretable model based on graph learning for diagnosis of Parkinson's disease with voice-related EEG.

Parkinson's disease (PD) exhibits significant clinical heterogeneity, presenting challenges in the identification of reliable electroencephalogram (EEG) biomarkers. Machine learning techniques have been integrated with resting-state EEG for PD diagnosis, but their practicality is constrained by the interpretable features and the stochastic nature of resting-state EEG. The present study proposes a novel and interpretable deep learning model, graph signal processing-graph convolutional networks (GSP-GCNs), using event-related EEG data obtained from a specific task involving vocal pitch regulation for PD diagnosis. By incorporating both local and global information from single-hop and multi-hop networks, our proposed GSP-GCNs models achieved an averaged classification accuracy of 90.2%, exhibiting a significant improvement of 9.5% over other deep learning models. Moreover, the interpretability analysis revealed discriminative distributions of large-scale EEG networks and topographic map of microstate MS5 learned by our models, primarily located in the left ventral premotor cortex, superior temporal gyrus, and Broca's area that are implicated in PD-related speech disorders, reflecting our GSP-GCN models' ability to provide interpretable insights identifying distinctive EEG biomarkers from large-scale networks. These findings demonstrate the potential of interpretable deep learning models coupled with voice-related EEG signals for distinguishing PD patients from healthy controls with accuracy and elucidating the underlying neurobiological mechanisms.

Closed-loop transcutaneous auricular vagus nerve stimulation for the improvement of upper extremity motor function in stroke patients: a study protocol.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has garnered attention for stroke rehabilitation, with studies demonstrating its benefits when combined with motor rehabilitative training or delivered before motor training. The necessity of concurrently applying taVNS with motor training for post-stroke motor rehabilitation remains unclear. We aimed to investigate the necessity and advantages of applying the taVNS concurrently with motor training by an electromyography (EMG)-triggered closed-loop system for post-stroke rehabilitation. Methods: We propose a double-blinded, randomized clinical trial involving 150 stroke patients assigned to one of three groups: concurrent taVNS, sequential taVNS, or sham control condition. In the concurrent group, taVNS bursts will synchronize with upper extremity motor movements with EMG-triggered closed-loop system during the rehabilitative training, while in the sequential group, a taVNS session will precede the motor rehabilitative training. TaVNS intensity will be set below the pain threshold for both concurrent and sequential conditions and at zero for the control condition. The primary outcome measure is the Fugl-Meyer Assessment of Upper Extremity (FMA-UE). Secondary measures include standard upper limb function assessments, as well as EMG and electrocardiogram (ECG) features. Ethics and dissemination: Ethical approval has been granted by the Medical Ethics Committee, affiliated with Zhujiang Hospital of Southern Medical University for Clinical Studies (2023-QX-012-01). This study has been registered on ClinicalTrials (NCT05943431). Signed informed consent will be obtained from all included participants. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings. Discussion: This study represents a pioneering effort in directly comparing the impact of concurrent taVNS with motor training to that of sequential taVNS with motor training on stroke rehabilitation. Secondly, the incorporation of an EMG-triggered closed-loop taVNS system has enabled the automation and individualization of both taVNS and diverse motor training tasks-a novel approach not explored in previous research. This technological advancement holds promise for delivering more precise and tailored training interventions for stroke patients. However, it is essential to acknowledge a limitation of this study, as it does not delve into examining the neural mechanisms underlying taVNS in the context of post-stroke rehabilitation.

Increased Adrenocorticotropic Hormone Levels Predict Recovery of Consciousness in Patients With Disorders of Consciousness.

The potential influence of pituitary-related hormones (including both pituitary gland and target gland hormones) on functional recovery after traumatic brain injury has been observed. However, the relationship between these hormones and the recovery of consciousness in patients with disorders of consciousness (DOC) remains unclear. In this retrospective and observational study, 208 patients with DOC were recruited. According to the Glasgow Outcome Scale (GOS) scores after 6 months, patients with DOC were categorized into two subgroups: a favorable prognosis subgroup (n = 38) comprising those who regained consciousness (GOS score ≥3), and a poor prognosis subgroup (n = 156) comprising those who remained in DOC (GOS score <3). Comparative analyses of pituitary-related hormone levels between the two subgroups were conducted. Further, a binary logistic regression analysis was conducted to assess the predictive value of pituitary-related hormones for the patients' prognosis. The favorable prognosis subgroup showed a significant increase in adrenocorticotropic hormone (ACTH) levels (p = 0.036). Moreover, higher ACTH levels and shorter days since injury were significantly associated with a better prognosis, with odds ratios (ORs) of 0.928 (95% confidence interval [CI] = 0.873-0.985, p = 0.014) and 1.015 (95% CI = 1.005-1.026, p = 0.005), respectively. A subsequent receiver operating characteristic (ROC) analysis demonstrated the potential to predict patients' prognosis with an area under the curve value of 0.78, an overall accuracy of 75.5%, a sensitivity of 77.5%, and a specificity of 66.7%. Our findings indicate that ACTH levels could serve as a clinically valuable and convenient predictor for patients' prognosis.

Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord.

Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal herb with various pharmacological activities, such as anti-inflammatory and analgesic properties. However, the underlying mechanisms of these effects are not fully understood. In the present study, we aimed to investigate DAP's anti-inflammatory and analgesic effects and explore the underlying mechanisms of action. The NP model was established as chronic constrictive injury (CCI) of the sciatic nerve, and pain sensitivity was evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). The activation of microglia in the spinal dorsal horn was measured via immunofluorescence staining. Protein levels were measured using a western blot assay. Using a mass-spectrometry proteomics platform and an LC-MS/MS-based metabolomics platform, proteins and metabolites in spinal cord tissues were extracted and analyzed. DAP treatment ameliorated the MWT and TWT in CCI rats. The expression of IL-1ß, IL-6, and TNF-α was inhibited by DAP treatment in the spinal cords of CCI rats. Moreover, the activation of microglia was suppressed after DAP treatment. The elevation in the levels of P2X4, IRF8, IRF5, BDNF, and p-P38/P38 in the spinal cord caused by CCI was inhibited by DAP. Proteomics and metabolomics results indicated that DAP ameliorated the imbalance of glycerophospholipid metabolism in the spinal cords of CCI rats. DAP can potentially ameliorate NP by regulating microglial responses and glycerophospholipid metabolism in the CCI model. This study provides a pharmacological justification for using DAP in the management of NP.

Individualized music induces theta-gamma phase-amplitude coupling in patients with disorders of consciousness.

Objective: This study aimed to determine whether patients with disorders of consciousness (DoC) could experience neural entrainment to individualized music, which explored the cross-modal influences of music on patients with DoC through phase-amplitude coupling (PAC). Furthermore, the study assessed the efficacy of individualized music or preferred music (PM) versus relaxing music (RM) in impacting patient outcomes, and examined the role of cross-modal influences in determining these outcomes. Methods: Thirty-two patients with DoC [17 with vegetative state/unresponsive wakefulness syndrome (VS/UWS) and 15 with minimally conscious state (MCS)], alongside 16 healthy controls (HCs), were recruited for this study. Neural activities in the frontal-parietal network were recorded using scalp electroencephalography (EEG) during baseline (BL), RM and PM. Cerebral-acoustic coherence (CACoh) was explored to investigate participants' abilitiy to track music, meanwhile, the phase-amplitude coupling (PAC) was utilized to evaluate the cross-modal influences of music. Three months post-intervention, the outcomes of patients with DoC were followed up using the Coma Recovery Scale-Revised (CRS-R). Results: HCs and patients with MCS showed higher CACoh compared to VS/UWS patients within musical pulse frequency (p = 0.016, p = 0.045; p < 0.001, p = 0.048, for RM and PM, respectively, following Bonferroni correction). Only theta-gamma PAC demonstrated a significant interaction effect between groups and music conditions (F (2,44) = 2.685, p = 0.036). For HCs, the theta-gamma PAC in the frontal-parietal network was stronger in the PM condition compared to the RM (p = 0.016) and BL condition (p < 0.001). For patients with MCS, the theta-gamma PAC was stronger in the PM than in the BL (p = 0.040), while no difference was observed among the three music conditions in patients with VS/UWS. Additionally, we found that MCS patients who showed improved outcomes after 3 months exhibited evident neural responses to preferred music (p = 0.019). Furthermore, the ratio of theta-gamma coupling changes in PM relative to BL could predict clinical outcomes in MCS patients (r = 0.992, p < 0.001). Conclusion: Individualized music may serve as a potential therapeutic method for patients with DoC through cross-modal influences, which rely on enhanced theta-gamma PAC within the consciousness-related network.

Effects of 10 Hz individualized repetitive transcranial magnetic stimulation on patients with disorders of consciousness: a study protocol for an exploratory double-blind crossover randomized sham-controlled trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, has shown potentials for consciousness recovery of patients with disorders of consciousness (DoC), as, to a certain extent, it is effective in regulating the excitability of central nervous system. However, it is difficult to achieve satisfactory effect with "one size fits all" rTMS treatment due to different clinical conditions of patients. There is an urgent need to develop individualized strategy to improve the effectiveness of rTMS on patients with DoC. METHODS: Our protocol is a randomized double-blind sham-controlled crossover trial that includes 30 DoC patients. Each patient will received 20 sessions, in which 10 sessions will be rTMS-active stimulus, and the other 10 sessions will be sham stimulus, separated by no less than 10 days' washout period. The rTMS-active will include 10 Hz rTMS over the individualized-targeted selection area for each patient according to the different insult regions of the brain. Coma Recovery Scale-Revised (CRS-R) will be used as primary outcome at baseline, after the first stage of stimulation, at the end of the washout period, and after the second stage of stimulation. Secondary outcomes will be measured at the same time, including efficiency, relative spectral power, and functional connectivity of high-density electroencephalograph (EEG). Adverse events will be recorded during the study. DISCUSSION: rTMS has obtained grade A evidence in treating patients with several central nervous system diseases, and there has been some evidence showing partial improvement on level of consciousness in DoC patients. However, the effectiveness of rTMS in DoC is only 30~36%, mostly due to the non-specific target selection. In this protocol, we present a double-blind crossover randomized sham-controlled trial based on the individualized-targeted selection strategy that aims to study the effectiveness of rTMS therapy for DoC, and the result may provide new insights to non-invasive brain stimulation. TRIAL REGISTRATION: ClinicalTrials.gov : NCT05187000. Registered on January 10, 2022.

Repetitive transcranial magnetic stimulation over the posterior parietal cortex improves functional recovery in nonresponsive patients: A crossover, randomized, double-blind, sham-controlled study.

Background: Recent studies have shown that patients with disorders of consciousness (DoC) can benefit from repetitive transcranial magnetic stimulation (rTMS) therapy. The posterior parietal cortex (PPC) is becoming increasingly important in neuroscience research and clinical treatment for DoC as it plays a crucial role in the formation of human consciousness. However, the effect of rTMS on the PPC in improving consciousness recovery remains to be studied. Method: We conducted a crossover, randomized, double-blind, sham-controlled clinical study to assess the efficacy and safety of 10 Hz rTMS over the left PPC in unresponsive patients. Twenty patients with unresponsive wakefulness syndrome were recruited. The participants were randomly divided into two groups: one group received active rTMS treatment for 10 consecutive days (n = 10) and the other group received sham treatment for the same period (n = 10). After a 10-day washout period, the groups crossed over and received the opposite treatment. The rTMS protocol involved the delivery of 2000 pulses/day at a frequency of 10 Hz, targeting the left PPC (P3 electrode sites) at 90% of the resting motor threshold. The primary outcome measure was the JFK Coma Recovery Scele-Revised (CRS-R), and evaluations were conducted blindly. EEG power spectrum assessments were also conducted simultaneously before and after each stage of the intervention. Result: rTMS-active treatment resulted in a significant improvement in the CRS-R total score (F = 8.443, p = 0.009) and the relative alpha power (F = 11.166, p = 0.004) compared to sham treatment. Furthermore, 8 out of 20 patients classified as rTMS responders showed improvement and evolved to a minimally conscious state (MCS) as a result of active rTMS. The relative alpha power also significantly improved in responders (F = 26.372, p = 0.002) but not in non-responders (F = 0.704, p = 0.421). No adverse effects related to rTMS were reported in the study. Conclusions: This study suggests that 10 Hz rTMS over the left PPC can significantly improve functional recovery in unresponsive patients with DoC, with no reported side effects. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05187000.

Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization.

Neuropathic pain (NP) is a common pain disease that seriously affects the quality of life and physical and mental health of patients. Daphnetin is extracted from the Daphne giraldii Nitsche and has the structure of 7,8-dihydroxy coumarin. As a natural product, daphnetin displays a wide range of pharmacological activities, such as analgesia and anti-inflammatory activities, but whether it is able to improve NP through anti-inflammatory effects is unknown. Therefore, this paper intends to investigate the mechanism of daphnetin in improving NP rats affected by the intrathecal injection of tumor necrosis factor-α (TNF-α) from the perspective of anti-inflammation. Our results showed that daphnetin significantly improved hyperalgesia in NP rats. Daphnetin inhibited the activation and polarization of glial cells and neurons in the spinal cord of NP rats and reduced the expression of mRNA and protein of inflammatory factors and chemokine pairs in the spinal cord. Daphnetin inhibited the polarization of human microglia cell 3 (HMC3) cells and human glioma cells (U251) cells toward M1 microglia and A1 astrocytes, respectively, and induced the conversion of M1 microglia and A1 astrocytes to M2 microglia and A2 astrocytes, respectively. In conclusion, daphnetin ameliorates NP by inhibiting the expression of inflammatory factors and chemokines and the polarization of glial cells in the spinal cord of NP rats. This study provides a theoretical basis for the treatment of NP with daphnetin to expand the clinical application of daphnetin.

Olfactory response is a potential sign of consciousness: electroencephalogram findings.

Objective: This study aimed to explore whether olfactory response can be a sign of consciousness and represent higher cognitive processing in patients with disorders of consciousness (DoC) using clinical and electroencephalogram data. Methods: Twenty-eight patients with DoC [13 vegetative states (VS)/unresponsive wakefulness syndrome (UWS) and 15 minimally conscious states (MCS)] were divided into two groups: the presence of olfactory response (ORES) group and the absence of olfactory response (N-ORES) group according to behavioral signs from different odors, i.e., vanillin, decanoic acid, and blank stimuli. We recorded an olfactory task-related electroencephalogram (EEG) and analyzed the relative power and functional connectivity at the whole-brain level in patients with DoC and healthy controls (HCs). After three months, the outcomes of DoC patients were followed up using the coma recovery scale-revised (CRS-R). Results: A significant relationship was found between olfactory responses and the level of consciousness (χ2(1) = 6.892, p = 0.020). For olfactory EEG, N-ORES patients showed higher theta functional connectivity than ORES patients after stimulation with vanillin (p = 0.029; p = 0.027). Patients with N-ORES showed lower alpha and beta relative powers than HCs at the group level (p = 0.019; p = 0.033). After three months, 62.5% (10/16) of the ORES patients recovered consciousness compared to 16.7% (2/12) in the N-ORES group. The presence of olfactory response was significantly associated with an improvement in consciousness (χ2(1) = 5.882, p = 0.023). Conclusion: Olfactory responses should be considered signs of consciousness. The differences in olfactory processing between DoC patients with and without olfactory responses may be a way to explore the neural correlates of olfactory consciousness in these patients. The olfactory response may help in the assessment of consciousness and may contribute to therapeutic orientation.

Is frontoparietal electroencephalogram activity related to the level of functional disability in patients emerging from a minimally conscious state? A preliminary study.

Objective: When regaining consciousness, patients who emerge from a minimally conscious state (EMCS) present with different levels of functional disability, which pose great challenges for treatment. This study investigated the frontoparietal activity in EMCS patients and its effects on functional disability. Materials and methods: In this preliminary study, 12 EMCS patients and 12 healthy controls were recruited. We recorded a resting-state scalp electroencephalogram (EEG) for at least 5 min for each participant. Each patient was assessed using the disability rating scale (DRS) to determine the level of functional disability. We analyzed the EEG power spectral density and sensor-level functional connectivity in relation to the patient's functional disability. Results: In the frontoparietal region, EMCS patients demonstrated lower relative beta power (P < 0.01) and higher weighted phase lag index (wPLI) values in the theta (P < 0.01) and gamma (P < 0.01) bands than healthy controls. The frontoparietal theta wPLI values of EMCS patients were positively correlated with the DRS scores (r s = 0.629, P = 0.029). At the whole-brain level, EMCS patients only had higher wPLI values in the theta band (P < 0.01) than healthy controls. The whole-brain theta wPLI values of EMCS patients were also positively correlated with the DRS scores (r s = 0.650, P = 0.022). No significant difference in the power and connectivity between the frontoparietal region and the whole brain in EMCS patients was observed. Conclusion: EMCS patients still experience neural dysfunction, especially in the frontoparietal region. However, the theta connectivity in the frontoparietal region did not increase specifically. At the level of the whole brain, the same shift could also be seen. Theta functional connectivity in the whole brain may underlie different levels of functional disability.

Solvent-free processing of eco-friendly magnetic and superhydrophobic absorbent from all-plant-based materials for efficient oil and organic solvent sorption.

The unique features of bioresources such as cellulose and bio-wax include renewability, biodegradability, low cost, and abundance on Earth. Therefore, their efficient use is essential for a sustainable economy. Herein, we report a facile method for the surface modification of pretreated cotton with a bio-wax emulsion in water and Fe3O4 nanoparticles to fabricate a green, durable, magnetic, and superhydrophobic/superoleophilic absorbent for the sorption of oil and organic solvents. Magnetic superhydrophobic cotton (MSC) was successfully prepared via a simple two-step dip-coating method without using any toxic organic reagents. The as-prepared MSC was used to selectively absorb various types of oils and organic solvents up to approximately 20-50 times its own weight. Furthermore, it exhibited a stable magnetic responsivity and high reusability in oil/water separation cycles. In addition, the removal and collection of the absorbed oil/organic solvents were easily achieved with distillation and a vacuum air pump. Moreover, the as-prepared MSC was used in a heavy oil/water gravity-separation filter system and in the continuous collection of a light oil from water surfaces using a pump. The proposed concept may provide a green and sustainable strategy for fabricating superhydrophobic/superoleophilic materials for efficient sorption of oils and organic solvents.

The influence of white matter hyperintensity on cognitive impairment in Parkinson's disease.

The aim of this meta-analysis was to review systematically and to identify the relationship between the severity and location of white matter hyperintensities (WMHs) and the degree of cognitive decline in patients with Parkinson's disease (PD). We searched the PubMed, EMBASE, Web of Science, Ovid, and Cochrane Library databases for clinical trials of the severity and location of WMHs on the degree of cognitive impairment in PD through October 2020. We conducted the survey to compare the association of WMH burden in patients with PD with mild cognitive impairment (PD-MCI) versus those with normal cognition (PD-NC) and in patients with PD with dementia (PDD) versus those with PD without dementia (PD-ND). Nine studies with PD-MCI versus PD-NC and 10 studies with PDD versus PD-ND comparisons were included. The WMH burden in PD-MCI patients was significantly different compared to that in PD-NC patients (standard mean difference, SMD = 0.39, 95% CI: 0.12 to 0.66, p = 0.005), while there was no correlation shown in the age-matched subgroup of the comparison. In addition, PDD patients had a significantly higher burden of WMHs (SMD = 0.8, 95% CI: 0.44 to 1.71, p < 0.0001), especially deep white matter hyperintensities (SMD = 0.54, 95% CI: 0.36 to 0.73, p < 0.00001) and periventricular hyperintensities (SMD = 0.70, 95% CI: 0.36 to 1.04, p < 0.0001), than PD-NC patients, regardless of the adjustment of age. WMHs might be imaging markers for cognitive impairment in PDD but not in PD-MCI, regardless of age, vascular risk factors, or race. Further prospective studies are needed to validate the conclusions.

External cueing facilitates auditory-motor integration for speech control in individuals with Parkinson's disease.

Instructing individuals with Parkinson's disease (PD) to speak loudly and clearly with external cues leads to improvements of their speech in loudness, pitch, and articulatory movement, but the underlying neural mechanisms are largely unknown. The present event-related potential study investigated whether and how external cueing can facilitate auditory-motor control of speech production in PD. Individuals with PD and healthy controls produced sustained vowels with internal and external auditory cues while hearing their voice pitch-shifted -200 cents. Individuals with PD produced significantly larger vocal compensations than healthy controls in the internally cued condition and exhibited a significant decrease in the magnitudes of vocal compensations with external cueing. Moreover, individuals with PD produced significantly smaller N1 responses and larger P2 responses in the externally versus internally cued condition and exhibited a significant correlation between decreased vocal compensations and increased P2 amplitudes after external cueing. These findings provide the first neurobehavioral evidence that external auditory cueing can compensate for impaired auditory-motor processing of vocal feedback errors associated with PD in a top-down manner.

Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation.

The aim of this study is to investigate the role and mechanism of microglial NOX2 activation in minimally toxic dose of LPS and Syn-elicited synergistic dopaminergic neurodegeneration. NOX2+/+ and NOX2-/- mice and multiple primary cultures were treated with LPS and/or Syn in vivo and in vitro. Neuronal function and morphology were evaluated by uptake of related neurotransmitter and immunostaining with specific antibody. Levels of superoxide, intracellular reactive oxygen species, mRNA and protein of relevant molecules, and dopamine were detected. LPS and Syn synergistically induce selective and progressive dopaminergic neurodegeneration. Microglia are functionally and morphologically activated, contributing to synergistic dopaminergic neurotoxicity elicited by LPS and Syn. NOX2-/- mice are more resistant to synergistic neurotoxicity than NOX2+/+mice in vivo and in vitro, and NOX2 inhibitor protects against synergistic neurotoxicity through decreasing microglial superoxide production, illustrating a critical role of microglial NOX2. Microglial NOX2 is activated by LPS and Syn as mRNA and protein levels of NOX2 subunits P47and gp91 are enhanced. Molecules relevant to microglial NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-КBP50 as their mRNA and protein levels are elevated after treatment with LPS and Syn. Combination of exogenous and endogenous environmental factors with minimally toxic dose synergistically propagates dopaminergic neurodegeneration through activating microglial NOX2 and relevant signaling molecules, casting a new light for PD pathogenesis.

Iron deposition in substantia nigra: abnormal iron metabolism, neuroinflammatory mechanism and clinical relevance.

Parkinson disease (PD) is associated with multiple factors, including iron, which is demonstrated to deposit excessively in PD brains. We detected iron deposition by susceptibility weighted image (SWI) and measured the levels of iron metabolism-related proteins and inflammatory factors in cerebrospinal fluid (CSF) and serum of PD patients and control subjects. Clinical symptoms of PD were evaluated by series of rating scales. Relationships among above factors were analyzed. Results showed that corrected phase (CP) value of substantia nigra (SN) was significantly decreased in PD group compared to control group, hence, SN was the main region with excessive iron deposition. In PD group, ferritin was significantly elevated in CSF and reduced in serum compared to control group, and levels of ferritin in CSF and serum were both significantly and positively correlated with CP value of SN, thus, abnormal iron metabolism in central and peripheral systems was associated with iron deposition. CP value of SN in PD group was significantly and negatively correlated with interleukin-1ß level in CSF, so interleukin-1ß might be a neuroinflammatory factor produced by excessive iron in SN. Iron deposition in SN was significantly correlated with motor symptoms and part of non-motor symptoms of PD.

Temporal Lobe Epilepsy Alters Auditory-motor Integration For Voice Control.

Temporal lobe epilepsy (TLE) is the most common drug-refractory focal epilepsy in adults. Previous research has shown that patients with TLE exhibit decreased performance in listening to speech sounds and deficits in the cortical processing of auditory information. Whether TLE compromises auditory-motor integration for voice control, however, remains largely unknown. To address this question, event-related potentials (ERPs) and vocal responses to vocal pitch errors (1/2 or 2 semitones upward) heard in auditory feedback were compared across 28 patients with TLE and 28 healthy controls. Patients with TLE produced significantly larger vocal responses but smaller P2 responses than healthy controls. Moreover, patients with TLE exhibited a positive correlation between vocal response magnitude and baseline voice variability and a negative correlation between P2 amplitude and disease duration. Graphical network analyses revealed a disrupted neuronal network for patients with TLE with a significant increase of clustering coefficients and path lengths as compared to healthy controls. These findings provide strong evidence that TLE is associated with an atypical integration of the auditory and motor systems for vocal pitch regulation, and that the functional networks that support the auditory-motor processing of pitch feedback errors differ between patients with TLE and healthy controls.

Training of Working Memory Impacts Neural Processing of Vocal Pitch Regulation.

Working memory training can improve the performance of tasks that were not trained. Whether auditory-motor integration for voice control can benefit from working memory training, however, remains unclear. The present event-related potential (ERP) study examined the impact of working memory training on the auditory-motor processing of vocal pitch. Trained participants underwent adaptive working memory training using a digit span backwards paradigm, while control participants did not receive any training. Before and after training, both trained and control participants were exposed to frequency-altered auditory feedback while producing vocalizations. After training, trained participants exhibited significantly decreased N1 amplitudes and increased P2 amplitudes in response to pitch errors in voice auditory feedback. In addition, there was a significant positive correlation between the degree of improvement in working memory capacity and the post-pre difference in P2 amplitudes. Training-related changes in the vocal compensation, however, were not observed. There was no systematic change in either vocal or cortical responses for control participants. These findings provide evidence that working memory training impacts the cortical processing of feedback errors in vocal pitch regulation. This enhanced cortical processing may be the result of increased neural efficiency in the detection of pitch errors between the intended and actual feedback.