Although working memory (WM) is considered as an emergent property of the speech perception and production systems, the role of WM in sensorimotor integration during speech processing is largely unknown. We conducted two event-related potential experiments with female and male young adults to investigate the contribution of WM to the neurobehavioural processing of altered auditory feedback during vocal production. A delayed match-to-sample task that required participants to indicate whether the pitch feedback perturbations they heard during vocalizations in test and sample sequences matched, elicited significantly larger vocal compensations, larger N1 responses in the left middle and superior temporal gyrus, and smaller P2 responses in the left middle and superior temporal gyrus, inferior parietal lobule, somatosensory cortex, right inferior frontal gyrus, and insula compared with a control task that did not require memory retention of the sequence of pitch perturbations. On the other hand, participants who underwent extensive auditory WM training produced suppressed vocal compensations that were correlated with improved auditory WM capacity, and enhanced P2 responses in the left middle frontal gyrus, inferior parietal lobule, right inferior frontal gyrus, and insula that were predicted by pretraining auditory WM capacity. These findings indicate that WM can enhance the perception of voice auditory feedback errors while inhibiting compensatory vocal behavior to prevent voice control from being excessively influenced by auditory feedback. This study provides the first evidence that auditory-motor integration for voice control can be modulated by top-down influences arising from WM, rather than modulated exclusively by bottom-up and automatic processes. One outstanding question that remains unsolved in speech motor control is how the mismatch between predicted and actual voice auditory feedback is detected and corrected. The present study provides two lines of converging evidence, for the first time, that working memory cannot only enhance the perception of vocal feedback errors but also exert inhibitory control over vocal motor behavior. These findings represent a major advance in our understanding of the top-down modulatory mechanisms that support the detection and correction of prediction-feedback mismatches during sensorimotor control of speech production driven by working memory. Rather than being an exclusively bottom-up and automatic process, auditory-motor integration for voice control can be modulated by top-down influences arising from working memory.

ObjectivesThere is an urgent need to develop therapeutic strategies to improve the treatment outcome of Alzheimer's disease. The treatment strategy of gene therapy mediated by nanocarrier systems brings new hope for the treatment of Alzheimer's disease. ROCK2 is involved in various pathological processes of Alzheimer's disease and may be a potential target for the treatment of Alzheimer's disease. Our previous study indicated that PEG-PEI/siROCK2 [polyethyleneglycol-polyethyleneimine deliver ROCK2-siRNA, (PPSR)] prevented Aβ 42 -induced neurotoxicity and showed a promising prospect for the treatment of Alzheimer's disease. However, whether PPSR has an effect on the microglial inflammation in Alzheimer's disease is still unclear.Materials and methods 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay was used to detect the cytotoxicity of PEG-PEI and PPSR in primary microglial cells. Real-time PCR and western blotting were used to assess the expression of ROCK2 and nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/caspase 1 pathway in primary microglial cells. ELISA assay was used to measure the effect of PPSR on attenuating the lipopolysaccharide (LPS) + Aβ-induced increase in IL-1β.Results PEG-PEI concentration less than 20 μg/ml and the N/P (molar ratio of PEG-PEI amino/siRNA phosphate) ratio of PPSR less than 50 showed no significant cytotoxicity in primary microglia cells. PPSR could effectively inhibit the expression of ROCK2 in primary microglial cells. A further study revealed that PPSR attenuates the LPS+Aβ-induced increase in IL-1β without affecting cell viability. In addition, we found that PPSR suppressed the Aβ-induced NLRP3/caspase 1 pathway in primary microglial cells. ConclusionPPSR inhibits Aβ 42 -induced microglial inflammation via NLRP3/caspase 1 pathway. NeuroReport

The supramarginal gyrus (SMG) has been implicated in auditory-motor integration for vocal production. However, whether the SMG is bilaterally or unilaterally involved in auditory feedback control of vocal production in a causal manner remains unclear. The present event-related potential (ERP) study investigated the causal roles of the left and right SMG to auditory-vocal integration using neuronavigated continuous theta burst stimulation (c-TBS). Twenty-four young adults produced sustained vowel phonations and heard their voice unexpectedly pitch-shifted by ±200 cents after receiving active or sham c-TBS over the left or right SMG. As compared to sham stimulation, c-TBS over the left or right SMG led to significantly smaller vocal compensations for pitch perturbations that were accompanied by smaller cortical P2 responses. Moreover, no significant differences were found in the vocal and ERP responses when comparing active c-TBS over the left vs. right SMG. These findings provide neurobehavioral evidence for a causal influence of both the left and right SMG on auditory feedback control of vocal production. Decreased vocal compensations paralleled by reduced P2 responses following c-TBS over the bilateral SMG support their roles for auditory-motor transformation in a bottom-up manner: receiving auditory feedback information and mediating vocal compensations for feedback errors.

Current models of speech motor control propose a role for the left inferior frontal gyrus (IFG) in feedforward control of speech production. There is evidence, however, that has implicated the functional relevance of the left IFG for the neuromotor processing of vocal feedback errors. The present event-related potential (ERP) study examined whether the left IFG is causally linked to auditory feedback control of vocal production with high-definition transcranial alternating current stimulation (HD-tACS). After receiving active or sham HD-tACS over the left IFG at 6 or 70 Hz, 20 healthy adults vocalized the vowel sounds while hearing their voice unexpectedly pitch-shifted by ±200 cents. The results showed that 6 or 70 Hz HD-tACS over the left IFG led to larger magnitudes and longer latencies of vocal compensations for pitch perturbations paralleled by larger ERP P2 responses than sham HD-tACS. Moreover, there was a lack of frequency specificity that showed no significant differences between 6 and 70 Hz HD-tACS. These findings provide first causal evidence linking the left IFG to vocal pitch regulation, suggesting that the left IFG is an important part of the feedback control network that mediates vocal compensations for auditory feedback errors.

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BackgroundAccumulating evidence has shown significant contributions of the right cerebellum to auditory-motor integration for vocal production. Whether the left cerebellum is likewise involved in vocal motor control, however, remains unclear.MethodsBy applying neuronavigated continuous and intermittent theta burst stimulation (cTBS/iTBS) over the left cerebellar lobule VII (Crus I), the present event-related potential (ERP) study investigated whether the left cerebellum exerts causal effects in modulating auditory feedback control of vocal pitch production. After receiving cTBS, iTBS, or sham stimulation over the left cerebellum, a group of fifteen young adults produced sustained vowels while hearing their voice unexpectedly shifted in pitch upwards or downwards by 200 cents. The effects of cerebellar stimulation were assessed by measuring the vocal and ERP (N1/P2) responses to pitch perturbations across the conditions.ResultsWhen compared to sham stimulation, cTBS or iTBS over the left cerebellar lobule VII (Crus I) led to no systematic changes in vocal compensations for pitch perturbations in auditory feedback. Also, the cortical N1/P2 responses did not vary significantly across the three stimulation sessions.ConclusionThese findings present the first neurobehavioral evidence suggesting that the left cerebellum is not causally associated with auditory feedback control of vocal production. Together with previously reported causal effects of the right cerebellum in modulating vocal pitch regulation, the present study lends support to the hypothesis that there is a functional lateralization of the cerebellum in vocal motor control though auditory feedback.

In speech processing, information related to the speech motor command and sensory re-afference can be stored in working memory (WM) within a feedback circuit and recalled when needed to adjust the motor activity. Whether WM facilitates the online monitoring of speech motor control, however, remains unclear. The present event-related potential study sought to examine the impact of WM on the auditory-motor processing of pitch feedback errors. Participants sustained a vowel phonation while hearing their voice pitch-shifted + 200 or + 500 cents five times. In the WM task, participants were asked to determine whether the sequence of 5 pitch shifts was different or not between two consecutive vocalizations. In the control task, they did nothing but maintaining their vocalizations steady when exposed to pitch-shifted auditory feedback. The behavioral results revealed a significant increase of vocal responses in the WM task as compared to the control task. At the cortical level, the WM task elicited significantly larger N1 responses and smaller P2 responses than the control task. Taken together, these findings demonstrate the influence of WM on the neurobehavioral responses to pitch-shifted voice auditory feedback, indicating that WM can facilitate the detection and correction of pitch feedback errors in vocal motor control.

Considerable evidence has shown that experienced singers are capable of voluntarily suppressing vocal compensations for consistent pitch perturbations in auditory feedback. Our recent behavioral study found that singers also compensated for brief pitch perturbations to a lesser degree than nonsingers in an involuntary manner. In the present event-related potential study, we investigated the neural correlates of involuntary vocal pitch regulation in experienced singers. All participants were instructed to vocalize the vowel sounds while their voice was unexpectedly shifted in pitch by –50 and –200 cents. The results revealed decreased cortical N1 and P2 responses to pitch perturbations and reduced involuntary vocal compensations for singers when compared to nonsingers. Moreover, larger vocal responses were significantly correlated with smaller cortical P2 responses for nonsingers, whereas this brain–behavior relationship did not exist for singers. These findings demonstrate that the cortical processing of involuntary auditory-motor integration for vocal pitch regulation can be shaped as a function of singing experience, suggesting that experienced singers may be less influenced by auditory feedback and rely more on somatosensory feedback or feedforward control as a consequence of singing training as compared to nonsingers.