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Frontiers | A Lower in Hemodynamic Response within the Proper Postcentral Cortex Is Related With Therapy-Resistant Auditory Verbal Hallucinations in Schizophrenia: An NIRS Research


Auditory verbal hallucinations (AVHs) are characterised because the experiences of listening to a voice or every other sounds for languages beneath the situations of aware state with no exterior stimulus (McCarthy-Jones and Resnick, 2014; Upthegrove et al., 2016). As essentially the most distinguished and burdensome signs of schizophrenia (SCZ), the prevalence of AVH reported charges of 60–80% (Alderson-Day et al., 2015). Nonetheless, roughly 30% of sufferers with AVH [treatment-resistant auditory verbal hallucinations, (TRAVHs)] aren’t responded effectively for present scientific remedies (Kennedy et al., 2014) and may trigger an elevated danger of violence, suicide, and hospitalization (Upthegrove et al., 2016; Dugré et al., 2018). From 2013 to 2018, the Worldwide Consortium on Hallucination Analysis (ICHR) steered that scientific and pathological options of AVH must be explored from all views (Waters, 2012; Jardri et al., 2019).

Presently, the underlying pathological mechanisms stay poorly understood, however an array of research have explored the neural correlations of AVH. For example, the useful neuroimaging proof explored the varied mind areas associated to AVH, a few of which had been concerned in inside speech technology, inside speech notion, and hallucinations processing (Stephane et al., 2001; Jardri et al., 2011; Kühn and Gallinat, 2012). In response to cognitive neurophysiology, inside speech has performed an vital position in a collection of theories of AVH in sufferers with SCZ (Shergill, 2003; Langland-Hassan, 2010; Wayne, 2012). One distinguished speculation means that inside speech fails to be labeled as internally generated, and as an alternative being perceived as an autonomous, non-self-voice (Jones, 2010). The neurological proof of inside speech mannequin concerned in left inferior frontal gyrus, bilateral temporal cortex, the supplementary motor space, premotor cortex, precentral, postcentral gyri, inferior parietal lobe, proper insula, and posterior cerebellar cortex bilaterally (Moseley et al., 2013; Curčić-Blake et al., 2017). Different outcomes displayed that AVH could come up from the irregular activation within the left superior temporal area and the left prefrontal cortex in the course of the processing of inside speech (Allen et al., 2007; Simons et al., 2010; Jardri et al., 2011). These above analysis displayed the neural activation related to AVH and inside speech had been discovered to supply extra convincing proof for the dysfunction of inside speech in sufferers with AVH. Based mostly on these findings, we hypothesized that useful abnormalities within the prefrontal and temporal cortex, as measured with useful near-infrared spectroscopy (fNIRS), underly TRAVH amongst sufferers with SCZ, supplying extra proof to have a greater understanding of the inside speech mannequin of AVH.

Practical near-infrared spectroscopy (fNIRS) (Herrmann et al., 2003) is a non-invasive imaging machine to guage mind operate, which has a number of benefits. fNIRS is simple to arrange, requires minimal, constrains, and doesn’t occupy a big area (Wei et al., 2020). Moreover, it’s protected, nonrestrictive, quiet, and economical for measurement (Ferrari and Quaresima, 2012). fNIRS alerts are believed to evaluate the neuronal exercise in response to a phenomenon often called neurovascular coupling (Gsell et al., 2000) and have robust correlations of blood oxygenation level-dependent (BOLD) alerts measured by fMRI (Sasai et al., 2012). Furthermore, fNIRS is much less delicate to movement artifacts and might be operated with out the acoustic scanner noise, which is extra appropriate for evaluating sufferers with AVH throughout associated duties (Ehlis et al., 2014). fNIRS can monitor each oxy- and deoxy-hemoglobin ranges within the cerebral cortex. For the reason that oxy modifications are better than deoxy-hemoglobin, oxy-hemoglobin is used because the mind exercise marker (Ferrari and Quaresima, 2012), whereas the verbal fluency job (VFT) is taken into account because the delicate indicators of language operate and frontal and temporal lobe operate, equivalent to a number of high-level cognitive course of, together with govt operate, consideration, inhibition, and dealing reminiscence, which has been proposed as an evaluation measure of useful impairment and sickness severity (Herrmann et al., 2003; Sasai et al., 2012; Koike et al., 2013). As well as, numerous fNIRS research have explored and in contrast the prefrontal cortex activation between sufferers with SCZ and wholesome management (HC) by VFT. Earlier findings confirmed that sufferers with SCZ had decreased oxy-hemoglobin within the bilateral prefrontal and temporal cortices in the course of the VFT job (Suto et al., 2004; Takizawa et al., 2008, 2014; Koike et al., 2013, 2017; Kumar et al., 2017), which indicated that VFT is a broadly accepted cognitive job for elucidating mind dysfunction associated to psychotic state. Amongst sufferers with SCZ, the symptom of AVH was related to the decreases within the cerebral blood move within the mind areas, together with postcentral gyri (inside speech manufacturing) (Tremblay et al., 2003) and proper supplementary motor space (inside speech imagery) (McGuire et al., 1995; Raij and Riekki, 2012), in addition to the bilateral dorsolateral prefrontal cortices (inside speech monitoring) (Cui et al., 2017). The grey matter density discount in proper postcentral gyri was discovered to be particularly negatively associated to the severity of AVH(García-Martí et al., 2008). Whereas, such research had been argued to favor that sufferers with SCZ with AVH and with out AVH confirmed considerably decreased ReHo within the bilateral postcentral gyrus (Zhuo et al., 2016), primarily based on the totally different outcomes, it’s much more vital to know whether or not the AVH-related mind area, equivalent to postcentral gyri, is the widespread neural substance underlying each the inside speech and AVH. Particularly, for SCZ-TRAVH, clarification of neural mechanisms is of nice scientific significance for therapy. Due to this fact, within the current examine, we utilized multi-channel fNIRS to analyze whether or not the symptom of TRAVH is related to useful alterations within the brains of sufferers with SCZ throughout VFT and the underlying neurological mechanisms for the inside speech associated to AVH.



A complete of 100 and three members (≥18 years outdated) had been included on this examine. Sufferers with TRAVH (n = 38 members) had skilled persecutory voices not less than 12 months and never reply to not less than two anti-psychotic trials of anti-psychotic medicine at equal doses to 600 mg/day of chlorpromazine. Sufferers with SCZ with out AVH (SCZ-nAVH) (n = 35 members) didn’t expertise AVH or had been absolutely remitted from AVH up to now yr. The entire sufferers utterly glad the DSM-V diagnostic standards for SCZ, whereby the structured scientific interview for DSM-V (SCI-D) was carried out by two skilled psychiatrists. Exclusion standards had been as follows: (1) any change in dose of anti-psychotic medicine in latest 3 months; (2) electroconvulsive remedy inside the previous 6 months; (3) alcohol or substance dysfunction; (4) traumatic mind harm; and (5) neurological impairment or mental incapacity. HC (n = 30) reported no previous or present of Axis I or II problems, and no historical past of Axis I dysfunction in first- or second-degree members of the family. HCs had been excluded if they’d the next situations: (1) natural illness; (2) alcohol abuse or drug dependence; (3) acquired psychotherapy up to now; and (4) different situations that disqualified the topic from the examine, as decided by the investigators. For sufferers with SCZ, we used Optimistic and Unfavorable Syndrome Scale (PANSS) (Lewine et al., 1983) to guage scientific signs. The degrees of functioning had been evaluated utilizing the modified World Evaluation of Functioning (GAF) (Asahi et al., 2004; Okada et al., 2016). The severity of the AVH was quantified by the size of The Psychotic Symptom Ranking Scales, auditory hallucinations (PSYRATS-AH) (Haddock et al., 1999) and Optimistic and Unfavorable Syndrome Scale, hallucinations merchandise (PANSS-P3). This examine has been authorized by the Ethics Committee of First Hospital of Shanxi Medical College (K047). Earlier than participation within the examine, all of the members had been capable of learn, perceive the consent type, and signed the knowledgeable consent.

Verbal Fluency Process

We adopted a Chinese language model of phonological VFT (Wei et al., 2020). This measurement was taken beneath a quiet atmosphere. Individuals had been requested to stay seated with their eyes open, keep away from extreme physique, reduce head actions, and give attention to a cross-displayed in the course of the measurements. It comprised a 30-s pre-task interval, a 60-s job interval, and a 70-s post-task interval. Through the pre- and post-task durations, the members had been requested to consistently say “1, 2, 3, 4, 5” repeatedly. Through the job interval, the members had been requested to generate as many four-character idioms or phrases as attainable, which start with the designated Chinese language characters (equivalent to, “大,” “白,” and “天,” indicating massive, white, and sky, respectively). There was a complete of three cue characters that had been modified each 20 s in the course of the 60-s job interval. The variety of distinctive phrases was recorded because the VFT job efficiency.

NIRS Measurement

A 52-channel fNIRS system (ETG-4100. Hitachi Medical Co., Tokyo, Japan) makes use of 2 NIR mild wavelengths (695 and 830 nm) to measure the hemodynamic responses within the prefrontal cortices and superior temporal cortices (FOIRE-4100, Hitachi Medical Co, Japan). This method had 16 mild detectors and 17 mild emitters, all of which had been organized in a 3 × 11 array to type 52 measurement channels in response to the worldwide 10–20 system. This association allowed for hemodynamic response lined primarily in the complete bilateral prefrontal cortices, and the anterior and superior elements of the temporal cortex to be measured.

NIRS Sign Evaluation

The near-infrared spectroscopy alerts had been processed with the NIRS-SPM toolbox (Jang et al., 2009; Ye et al., 2009), which is a MATLAB-based software program package deal for statistical evaluation. NIRS_SPM relies on the overall linear mannequin (GLM) methodology of knowledge evaluation. The GLM methodology is a well-established regression methodology broadly used for fMRI knowledge evaluation and has additionally been utilized within the evaluation of fNIRS knowledge. The GLM consists of the variables Y, X, β, and ε, as follows: Y = βX + ε. Y represents the info really detected by fNIRS, consisting of the info matrix containing time collection and detection channels. X is the expected worth primarily based on the experimental design; this worth is obtained by convolving the hemodynamic response operate with the occasion sequence. β is the coefficient of match, which displays how a lot of the Y sign is attributable to the check matrix X. On this examine, it represents the extent of mind cortical useful exercise response attributable to VFT. Lastly, ε represents unexplained errors. fNIRS uncooked knowledge had been carried out utilizing a hemodynamic response operate (HRF) and discrete cosine remodel (DCT) to take away noise, such because the drift and synthetic noises (equivalent to head movement) (Brigadoi et al., 2014). In response to the earlier research, in contrast with the modifications in deoxygenated hemoglobin concentrations, oxygenated hemoglobin concentrations had been the extra delicate and dependable measures of fNIRS used for later evaluation (Strangman et al., 2003).

Statistical Evaluation

The Δβ worth of oxy-hemoglobin (VFT β worth minus baseline β worth) was used to evaluate the diploma of activation of the mind cortex induced throughout VFT job interval and analyzed utilizing SPSS v22.0 (SPSS Inc, Chicago, IL, USA). The info of categorical variables had been carried out utilizing the chi-square check. One-way evaluation of variance (ANOVA) with Bonferroni corrected submit hoc pairwise comparisons was then used to find out the impact of various teams on steady variables. For channels that exhibit vital variations within the submit hoc Bonferroni corrected check, Pearson’s correlation coefficient was carried out to find out the connection between the Δβ worth of oxy-hemoglobin and variety of phrases, PANSS-positive rating, -negative rating, normal psychopathology rating, P3 rating, GAF, and PSYRATS-AH rating. Then, a number of regression analyses had been carried out utilizing modifications in oxy-hemoglobin because the dependent variable and age, intercourse (males = 1, ladies = 2), the variety of phrases, PSYRATS-AH scores, PANSS subscores, P3 sores, and GAF scores because the unbiased variables. All exams had been two-tailed, and the obtained p-value was corrected by false discovery price (FDR) (Benjamini et al., 2001; Singh and Dan, 2006). P(FDR) < 0.05 was thought of statistically vital.


Demographic, Scientific, and Psychosocial Traits of All of the Individuals

This examine included 38 sufferers with SCZ-TRAVH, 35 sufferers with SCZ-nAVH, and 30 HCs. Desk 1 summarizes the samples of sociodemographic and scientific knowledge. The three totally different teams didn’t differ in gender, age, schooling years, sickness length, variety of phrases, PANSS rating, PANSS subscore, and GAF rating. PSYRATS-AH and PANSS P3 scores had been considerably increased within the SCZ-TRAVH group than within the SCZ-nAVH group (all p < 0.001) (Desk 1).

Desk 1. Demographic, scientific, and psychosocial traits of all members (n = 103).

Hemodynamic Response Through the VFT

One-way repeated-measures ANOVA confirmed that there have been vital variations in Δβ values among the many three teams at 26 channels (ch4, ch13–15, 18, 22, ch25–29, 32, ch35–39, ch43–51, F = 1.70 to 19.10, p < 0.043, FDR-corrected, Determine 1) distributed over the prefrontal–temporal cortical areas, whereas there have been no statistically vital variations in any of the opposite channels. The Δβ values within the above channels had been additional in contrast between teams (utilizing Bonferroni corrected submit hoc pairwise comparisons). The additional comparability outcomes confirmed that the Δβ values of 24 channels (ch13–15, 18, 22, 25, ch26–29, ch35–39, ch43–49, ch50–51) had been considerably decrease within the schizophrenia group (SCZ-TRAVH and/or SCZ-nAVH) than within the HC group (p < 0.026, FDR-corrected, Determine 2). As well as, the SCZ-TRAVH group has a decrease hemodynamic response at channel 22 of the suitable postcentral gyrus in comparison with the SCZ-nAVH group (p = 0.0029; Determine 2) and HC group (p = 0.0029; Determine 2), respectively, whereas no vital distinction was noticed on this channel between SCZ-nAVH group and HC group.

Determine 1. Three-dimensional cerebral maps of oxy-hemoglobin response patterns in the course of the job durations. The crimson and yellow colours of 26 channels exhibit vital modifications in meanΔβvalues of oxy-hemoglobin in the course of the VFT job interval among the many three teams, as decided utilizing one-way ANOVA exams (FDR-corrected p < 0.05).

Determine 2. Bonferroni corrected submit hoc pairwise comparability evaluation outcomes present vital distinction in meanΔβvalues of oxy-hemoglobin on 24 channels (ch13–15, ch18, ch22, ch25–29, ch35–39, ch43–51). Error bars signify customary errors (all FDR-corrected *p < 0.05; **p < 0.01; ***p < 0.001; SCZ-TRAVH and/or SCZ-nAVH vs. HC group).

Correlation Between Demographic Characters and FNIRS Variables

Inside the SCZ-TRAVH group, we noticed trend-level damaging correlations between the Δβ values of oxy-hemoglobin of the ch22 and P3 rating (r = −0.343, p = 0.035, FDR-uncorrected). Equally, a big affiliation was noticed between Δβ values of oxy-hemoglobin at channel 22 and the rating of the PSYRATS-AH scales (r = −0.577, p < 0.001). Additionally, a slight damaging correlation was discovered between the PANSS-positive rating and the Δβ values of oxy-hemoglobin at channel 22 (r = −0.440, p = 0.006). No different vital correlations had been discovered between Δβ values of oxy-hemoglobin at channel 22 and rating (PANSS-negative rating, PANSS normal psychopathology rating, GAF scores, and the variety of phrases). The affiliation between the Δβ values of channel 22 and PSYRATS-AH remained vital after controlling for age, intercourse (males = 1, ladies= 2), the variety of phrases, PANSS subscores, P3 sores, and GAF scores in a a number of regression evaluation (R2 = 0.382, adjusted R2 = 0.212, β = −0.636, t = −2.272, p = 0.031) (Determine 3A). For SCZ-nAVH group, there was no vital affiliation between rating (PSYRATS-AH and PANSS subscores) and the change of fNIRS alerts at channel 22 (all p > 0.05).

Determine 3. (A) The Δβ values of oxy-hemoglobin had been considerably related to severity of hallucinations on the channel 22, together with PSYRATS-AH, PANSS-positive rating, and P3 rating. (B) Common oxy-hemoglobin waveforms of three teams on the cortical areas. Vertical traces demarcate the beginning and finish of the VFT job interval.

Nonetheless, the typical waveforms of channel 22 of three teams illustrate that the rise in oxy-hemoglobin in the course of the VFT job interval was considerably increased within the sufferers with SCZ-nAVH and HC than within the sufferers with SCZ-TRAVH (Determine 3B). As well as, imply oxy-hemoglobin at channel 22 was related to the symptom of AVH. Taken collectively, the outcomes counsel that hemodynamic dysfunction in channel 22 appears to be related to TRAVH.


This examine used fNIRS to discover the affiliation between hemodynamic response within the prefrontal and temporal cortices and TRAVH symptom in sufferers with SCZ. Our outcomes indicated that sufferers with SCZ-TRAVH exhibited decrease activation in the suitable postcentral gyrus than did these with out the symptom of AVH.

First, by way of oxy-hemoglobin, our examine noticed that the SCZ-TRAVH and SCZ-nAVH group had decrease mind activation in intensive prefrontal and temporal cortices in distinction to the HC group, which had been much like the earlier fNIRS research displaying the decrease oxy-hemoglobin response in related mind cortices in the course of the associated job (Takizawa et al., 2008, 2014; Wei et al., 2020). As well as, the mind exercise of 24 channels within the SCZ-TRAVH group was decrease than that within the HC group, whereas the oxy-hemodynamic response of solely 18 channels within the SCZ-nAVH group was decrease. In response to the earlier fMRI research, hypoactivation of the bilateral prefrontal cortex and temporal cortices in sufferers with SCZ has been reported, which is related to confusion of imagined objects as perceptual occasions (Simons et al., 2006). Taken collectively, the outcomes steered that hemodynamic dysfunction within the prefrontal cortex and temporal cortices could also be extra intensive in sufferers with SCZ-TRAVH than sufferers with out AVH.

In our consequence, SCZ-TRAVH group have decrease hemodynamic response at channel 22 of the suitable postcentral gyrus in comparison with SCZ-nAVH group. This consequence was replicated within the fMRI examine that sufferers with AVH confirmed decreased cerebral blood move within the bilateral superior and postcentral gyri in contrast with sufferers with SCZ-nAVH (Cui et al., 2017). As well as, a big damaging affiliation emerged between the Δβ worth of oxy-hemoglobin within the area of ch22 and severity of AVH symptom [PSYRATS-AH score, PANSS-positive score, and P3 (hallucinations) score]. The affiliation between Δβ values of channel 22 and PSYRATS-AH remained vital after controlling for different scales scores and VFT efficiency in a a number of regression evaluation. This significant discovering partially agreed with earlier researches reported vital affiliation between the discount of bilateral postcentral gyrus quantity and the severity AVH in SCZ (García-Martí et al., 2008; Nenadic et al., 2010). It was not troublesome to search out that among the many above related scales, PSYRATS-AH had the best correlation, adopted by PANSS-positive rating. In response to the consensus, PSYRATS-AH is a extra detailed and multidimensional examination than PANSS and P3 for listening to voices, which had usually robust reliability and been broadly utilized in numerous scientific research of neural correlations of AVH (Ratcliff et al., 2011). Contemplating the best correlation of PSYRATS-AH with CH22 sign modifications, this will likely largely steered associations of decreased activation within the postcentral gyrus with the putative mechanisms by which psychotic signs are generated, particularly AVH. Moreover, the earlier fMRI research reported the suitable postcentral gyrus associated to AVH and could also be a brand new therapeutic goal sooner or later (van Lutterveld et al., 2013). Moreover, Zui Narita et al.’s analysis additional explored the potential utility of fNIRS for the prediction of results of tDCS on psychotic signs (Narita et al., 2018). Though the findings present totally different potential therapeutic mind areas, these outcomes help the idea that fNIRS could present a legitimate methodology to guage mind features primarily based on blood move, much like fMRI (Lee et al., 2018).

The mechanism by which mind exercise measured by fNIRS must be thought of in relation to affected by AVH signs. The postcentral gyrus considered one location of classically and first outlined somatosensory cortex (Skipper et al., 2005; Pérez-Bellido et al., 2018). A meta-analysis mirrored the affiliation of AVH with activation within the postcentral areas associated to subvocal speech (Kühn and Gallinat, 2012) and subsequently being thought of involving inside speech technology (Feinberg, 1978; Shergill et al., 2002), whereas the signs of AVH had been constantly related to the problems of technology of inside speech (inside verbal ideas) (McGuire et al., 1996; DeLisi, 2001). In response to different neuroimaging researches, inside speech-related mind area concerned within the left inferior frontal, the suitable pre- and postcentral, and each superior temporal gyri (Shergill et al., 2002). In addition to, one other latest examine additional demonstrated that the postcentral gyrus was concerned within the auditory data course of and even auditory hallucination signs (Joo et al., 2020). It appeared that the inside speech technology performed a job within the pathogenesis of AVH (McGuire et al., 1995). Taken along with the above neurological proof, the decreased activation of postcentral gyrus could underlie the idea for problems of inside speech technology and suggest alterations within the monitoring of inside speech, resulting in the next danger for affected by the symptom of AVH, partially according to inside speech mannequin of AVH.

On this examine, we give attention to a restricted group of SCZ-TRAVH whose AVH symptom was at a comparatively steady section to develop in-depth data of pathological options of AVH and the heterogeneous nature of this illness. Moreover, we used fNIRS to disclose irregular mind operate throughout VFT job, which was corresponded to the resting-state and task-state fMRI research‘ outcomes (van Lutterveld et al., 2013; Cui et al., 2017), which make fNIRS as an acceptable analysis software to discover the underlying neural alterations of sufferers with TRAVH throughout associated duties. Our vital discovering could promote the event within the design of the novel therapeutic methods for TRAVH and encourage the appliance of fNIRS evaluation to follow-up research with a bigger pattern dimension to discover the underlying neuroimaging mechanism and perceive the pathophysiological correlations of TRAVHs in SCZ.

Nonetheless, there are some clear limitations related to our analysis. First, affected person’s pattern sizes on this examine had been comparatively small for aiming to supply a particular activation sample for SCZ-TRAVH. Due to this fact, growing the pattern dimension may determine additional mind areas related to AVH. Second, though our researchers targeted on learning a restricted group of sufferers with SCZ with steady psycho-pathological options (AVH) proof against drug therapy to acquire the activation distinction in potential mind areas, we can’t absolutely rule out the medicinal results. Nonetheless, in response to Koike et al.’s examine (Koike et al., 2013), they emphasised that there is no such thing as a affiliation between fNIRS exercise of sufferers with SCZ and doses of medication. Moreover, there was no vital distinction in medicine therapy between the SCZ-TRAVH and SCZ-nAVH teams in our examine. As well as, we didn’t get hold of knowledge associated to cognitive signs in our members. Since cognitive signs are related to the prefrontal dysfunction for sufferers with SCZ, additional examine with an evaluation of cognitive signs is warranted.

The current multi-channel fNIRS examine confirmed an affiliation between TRAVH-induced hemodynamic impairments in the suitable postcentral gyrus and a historical past of TRAVH amongst sufferers with SCZ. These findings could assist to supply proof for the widespread theories concerning the “inside speech” and AVH, facilitating to do the design of novel therapeutic strategies. An additional examine is remained to discover the long-term outcomes of SCZ-TRAVH via the fNIRS measurement.


Our examine used NIRS expertise to discover and examine the irregular activation distinction in mind areas for sufferers with SCZ with TRAVH and nAVH. We discovered a damaging affiliation between the decreased activation of proper postcentral gyrus and severity of TRAVH. Additional, this examine equipped a attainable rationalization for the prevalence of TRAVH in SCZ from the inside speech insights, which can have implications for an early organic evidence-based intervention for TRAVH.

Information Availability Assertion

The uncooked knowledge supporting the conclusions of this text can be made obtainable by the authors, with out undue reservation. Requests to entry these datasets must be directed to

Ethics Assertion

Written knowledgeable consent was obtained from the person(s) for the publication of any probably identifiable photos or knowledge included on this article.

Creator Contributions

NL, YT, and SL contributed to the examine design and had been concerned in knowledge acquisition, evaluation, and interpretation. XL, DW, QL, and YX contributed to the examine design and knowledge interpretation. All authors participated within the drafting or crucial evaluation of the article, gave ultimate approval of the model to be printed, and agreed to be accountable for all elements of the work.


This work was supported by the Nationwide Pure Science Basis of China (81971601 and 81571319), the Nationwide Key Analysis and Growth Program of China (2016YFC1307004), the Wu Jieping Basis (320.6750.18283), the particular mission for guiding the transformation of scientific and technological achievements in Shanxi Province (201904D131020), and the Multidisciplinary Workforce for Cognitive Impairment of Shanxi Science and Know-how Innovation Coaching Workforce (201705D131027).

Battle of Curiosity

The authors declare that the analysis was carried out within the absence of any industrial or monetary relationships that could possibly be construed as a possible battle of curiosity.

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All claims expressed on this article are solely these of the authors and don’t essentially signify these of their affiliated organizations, or these of the writer, the editors and the reviewers. Any product that could be evaluated on this article, or declare that could be made by its producer, will not be assured or endorsed by the writer.



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