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- Springer Journals
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- 2018 The Author(s)
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- 1744-9081
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- 10.1186/s12993-017-0133-4
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Abstract
Background: Schizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ. Methods: To address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls. Results: We found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at 2 2 rs2249810 (χ = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01). Conclusions: These results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population. Keywords: CDNF2, Polymorphism, PANSS, Schizophrenia was 13-fold higher for SZ than the general population Background [5]. The core symptoms of SZ vary in terms of severity Schizophrenia (SZ) is a complex psychiatric disorder among patients [6]. Research on the genetic basis of SZ with an estimated heritability of 60–80% that affects has focused on identifying polymorphisms in candidate 1.0% of the global population [1–3]. Previous studies genes and linkage regions [7–10]. To date, 108 SZ-asso- have reported that the absolute risk of suicide in SZ to ciated gene loci have been identified in a genome-wide be 6.55% in male and 4.91% in female [4], and suicide association analysis (GWAS) of the largest sample size to date (36,989 cases vs. 113,075 controls) [11]. How- *Correspondence: jiangtz@nlpr.ia.ac.cn; lvx928@126.com 5 ever, others have reported that multiple genes contribute National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China weakly or moderately to SZ pathogenesis [12]. Identify- Department of Psychiatry of the Second Affiliated Hospital of Xinxiang ing SZ susceptibility genes among numerous candidates Medical University, No. 388, Jianshe Middle Road, Xinxiang 453002, China is an ongoing challenge. Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Behav Brain Funct (2018) 14:1 Page 2 of 7 Abnormal dopamine levels underlie SZ. Neurotrophic Han Chinese who were born and living in North Henan factors, such as brain-derived neurotrophic factor province. (BDNF), nerve growth factor, glial cell line-derived neu- Five SNPs were selected as described in our previ- rotrophic factor, and cerebral dopamine neurotrophic ous work [16, 17] and covered the 26974145–26995906 factor (CDNF), can repair and protect the dopaminer- genomic intron region on chromosome 10. In stage 1, gic system. Previous studies have shown that BDNF is genotyping was carried out as detailed in our earlier involved in the pathophysiology of SZ, with BDNF levels studies [16, 17] using Illumina GoldenGate assays on a reduced in the serum and cerebrospinal fluid of patients BeadStation 500G Genotyping System (Illumina, San [13]. CDNF has been shown to protect and repair the Diego, CA, USA). In stage 2, samples were genotyped dopaminergic system in rat models of Parkinson’s dis- using a standard Illumina genotyping protocol. ease (PD) [14], which is characterized by degeneration of Statistical analyses in this study were performed as dopaminergic neurons; it may thus have therapeutic ben- described in our previous papers [16, 17]. Power analy- efits [15]. However, the relationship between CDNF and ses were performed using the G*Power software to cal- SZ has not been previously investigated. We speculated culated (http://www.gpower.hhu.de/) for this study that CDNF is a susceptibility factor for SZ. We tested this [20, 21]. Genotype and allele frequencies were analyzed hypothesis by examining CDNF single nucleotide poly- using Haploview v.4.1. Hardy–Weinberg equilibrium morphisms (SNPs) in two study stages with independent was assessed with the χ test with one degree of freedom. sample sets. Associations between the five factors from the PANSS and different genotype carriers were evaluated by analy - Methods sis of variance. Bonferroni correction for multiple pair- Stage 1 samples were those from our previous pub- wise comparisons was conducted for the X × phenotype lications [16, 17], and included 528 paranoid SZ interaction to reduce the probability of false positives. patients (mean age: 27.32 ± 8.03 years old) and 528 P < 0.05 was considered statistically significant. The cor - healthy controls (mean age: 27.73 ± 8.01 years old) rected α′ (P = 0.01) is α (P = 0.05) divided by the number who were recruited from March 2005 to December of possible comparisons. 2008. Stage 2 samples included 142 SZ patients (para- noid, n = 122 and undifferentiated, n = 20; mean age: Results 29.28 ± 7.17 years old) and 173 healthy controls (mean To identify allelic variants of the CDNF2 gene that are age: 32.49 ± 7.43 years old) who were recruited from associated with SZ, we analyzed two sets of samples. May 2011 to December 2014. The sampling success rate for subjects and SNPs was SZ was diagnosed as previously described [16, 17] 99.84%. Power analyses revealed that the total sample according to the criteria listed in the Diagnostic and size (n = 1371) had a power of 0.96 to detect a small Statistical Manual of Mental Disorders Fourth Edition effect (r = 0.1–0.23), and a power of 1.00 to detect both (DSM-IV). Exclusion criteria were as follows: patients medium (r = 0.24–0.36) and large (r > 0.37) effects on had been diagnosed with other psychiatric disorders; genotype distributions. For allele frequency, the sam- or had organic brain disease, substance dependence, ple size (n = 2742) had the power (0.91–1.00) to detect severe medical complications, or neurological dis- small, medium, and large effects. eases. Family mental health history (FH) was defined None of the genotype distributions of the other four as at least one first- or second-degree relative of the SNPs significantly deviated from HWE except for SNP proband who met DSM-IV criteria for SZ or schizoaf- rs6506891. There were no significant differences in gen - fective disorder. The Positive and Negative Symptom otype and allele frequencies between SZ and controls Scale (PANSS) was used to evaluate psychotic syn- at five SNPs in stage 1 samples (P > 0.05, Table 1), even dromes. Five factors were derived from the PANSS, after subdividing by gender and FH (P > 0.05). How- including positive symptoms, negative symptoms, cog- ever, there were significant differences in genotype and nition, expression/anxiety, and excitement/hostility allele frequencies between SZ and controls at rs2249810, [18]. rs6506891, and rs2118343 in stage 2 samples. We also A total of 372 SZ patients (stage 1, n = 229 and stage 2, noted differences at rs2249810 when stage 1 and 2 sam - n = 143) who were not taking antipsychotic medications ples were combined. This association was present at were evaluated for psychotic syndromes using the PANSS rs2249810 in males (χ = 8.76; P = 0.03). To further ana- [19]. Inclusion and exclusion criteria for healthy controls lyze haplotype structures in this sample, we evaluated were as described our previous papers [16, 17]. These pairwise linkage disequilibrium (LD) of five SNPs in SZ subjects were screened by psychiatrists in simple non- patients and controls using standardized D′ and r val- structured interviews. All participants were unrelated ues. Haplotypes were identified at five SNPs of CDNF2 Yang et al. Behav Brain Funct (2018) 14:1 Page 3 of 7 Table 1 Genotype and allele frequencies of SNPs in the CDNF2 gene in patients with SZ and controls a c dbSNP ID Stage Allele (D/d) Patients Controls P value Combine P value b b n HWE (p) Genotype MAF n HWE (P) Genotype MAF DD Dd dd DD Dd dd Genotype Allele Genotype Allele rs2577074 1 G/A 528 0.35 144 253 131 0.49 528 0.12 140 281 107 0.469 0.14 0.09 0.43 0.89 2 142 0.58 44 73 25 0.18 173 0.32 41 93 39 0.225 0.28 0.13 rs2577075 1 A/G 527 0.37 143 253 131 0.49 527 0.13 140 280 107 0.469 0.15 0.29 0.15 0.14 2 142 0.58 44 73 25 0.18 170 0.22 40 93 37 0.218 0.30 0.15 rs2249810 1 G/A 528 0.18 186 242 100 0.42 528 0.43 189 261 78 0.395 0.18 0.38 0.04 0.03 2 139 0.83 63 62 14 0.10 172 0.65 59 81 32 0.186 0.04 0.01 rs6506891 1 T/A 526 0.00 285 143 98 0.32 526 0.00 299 151 76 0.288 0.19 0.38 0.78 0.41 2 142 0.93 64 63 15 0.11 173 0.81 58 83 32 0.185 0.04 0.01 rs2118343 1 C/G 528 0.83 309 191 28 0.23 526 0.32 318 187 21 0.218 0.56 0.41 0.76 0.45 2 142 0.53 97 42 3 0.02 173 0.18 101 58 14 0.081 0.03 0.02 Significant values has been emphasized by italic Major/minor allele, major and minor alleles are denoted by D and d, respectively Number of samples which are well genotyped P values in the parenthesis were analyzed with 10,000 random permutations Yang et al. Behav Brain Funct (2018) 14:1 Page 4 of 7 in stage 1 and 2 samples. The positions of these SNPs in Bonferroni correction (F = 4.05; P = 0.04). Other SNPs stage 2, LD structure, and D′ values for all variants are from stage 1 and 2 samples did not show any associations shown in Fig. 1. Five SNPs formed one LD block, yielding (P > 0.05). However, rs2118343 genotypes were signifi - four haplotypes; one of these (TGATC) differed signifi - cantly associated with negative factor scores when stage cantly between SZ and controls only in stage 2 samples 1 and 2 samples were combined (F = 4.396, P = 0.01). We (χ = 6.38; P = 0.01) (Table 2). found rs2118343 genotypes were associated with depres- To explore the association between CDNF2 varia- sion/anxiety and excitement/hostility scores in female tions and SZ symptoms, 371 first-onset SZ patients when subdivided by gender in combined samples after (stage 1, n = 228 and stage 2, n = 143) with complete Bonferroni correction (F = 4.39, 4.73; P = 0.04, 0.03, PANSS scores were selected from stages 1 and 2. Only respectively). rs2577075 genotypes were associated with cognition factor scores in stage 2 samples after Bonferroni correc- Discussion tion (F = 3.39; P = 0.03) (Table 3). We also only found This study investigated CDNF2 mutations associated with rs2577075 genotypes were associated with cognition SZ and associated symptoms in the Han Chinese popula- factor scores in female when subdivided by gender after tion. Significant differences were found in genotype and allele frequencies of rs2249810 between SZ patients and healthy controls, suggesting that CDNF2 is a susceptibil- ity gene for SZ. We also found that rs2118343 genotypes are associated with negative psychotic symptoms of SZ. CDNF has strong neuroprotective and restorative effects in animal models of PD [22], and protects dopa - minergic neurons in the 6-hydroxydopamine rat model [14, 23]. However, the genotype and allele frequencies of the CDNF SNPs rs1901650 and rs11259365 did not dif- fer between PD patients and controls; only the C allele of CDNF rs7094179, an intronic SNP, has been linked to PD susceptibility [24, 25]. Intron variant was relation to the CDNF2 gene organi- zation. CDNF2 can protect and repair the dopaminergic system, and may thus have an important role in PD [14, 26, 27]. Five SNPs of CDNF2 in our study were located in intron region of chromosome 10, which variation may lead to dopaminergic system disfunction. Mean- while, multiple SZ susceptibility loci have been found on chromosome 10 [7, 8]. In stage 1 samples, we did not detect any associations in paranoid SZ patients, possi- bly because we did not examine other SZ subtypes. We therefore included the undifferentiated subtype in the stage 2 analysis, and found that rs2249810 of CDNF2 may Fig. 1 Haplotype block structure of the CDNF2 gene in both SZ patients and healthy controls in stage 2 samples. The index associa- be a susceptibility locus in SZ. tion SNP is represented by a diamond. The colors of the remaining SZ is influenced by dopamine, glutamate, and seroto - SNPs (circles) indicate LD with the index SNP based on pairwise r nin neurotransmission systems. We previously reported values from our data associations between Solute carrier family 6 member 4 Table 2 Haplotypes of CDNF2 in stage 2 patients with SZ Haplotype Case (freq) Control (freq) Chi square P value Odds ratio (95% CI) CAGAG 157.87 (0.57) 169.89 (0.50) 2.25 0.13 1.29 (0.94–1.78) TGATC 45.87 (0.17) 82.00 (0.24) 6.38 0.01 0.61 (0.41–0.92) TGATG 43.00 (0.16) 57.90 (0.17) 0.30 0.58 0.88 (0.57–1.35) TGGAG 30.13 (0.11) 26.11 (0.08) 2.61 0.11 1.44 (0.83–2.51) Significant value has been emphasized by italic CI confidence interval Yang et al. Behav Brain Funct (2018) 14:1 Page 5 of 7 Table 3 Association analysis between five factors of PANSS and five SNPs of CDNF2 in patients with SZ SNP Genotype Total PANSS Positive Negative Depression/anxiety Cognition Excitement/hostility Stage 1 Stage 2 Stage 1 Stage 2 Stage 1 Stage 2 Stage 1 Stage 2 Stage 1 Stage 2 Stage 1 Stage 2 rs2577075 AA 80.46 ± 18.15 86.36 ± 8.49 20.22 ± 6.60 22.63 ± 5.53 17.02 ± 5.45 19.70 ± 3.39 14.39 ± 2.97 14.51 ± 2.28 16.73 ± 5.62 17.21 ± 3.93* 7.44 ± 3.53 6.93 ± 2.99 AG 81.24 ± 20.65 84.67 ± 11.44 20.49 ± 8.02 22.17 ± 5.95 17.76 ± 5.73 19.81 ± 3.25 13.70 ± 3.53 14.35 ± 2.75 16.67 ± 5.22 15.85 ± 3.71* 7.58 ± 4.03 7.22 ± 3.03 GG 84.45 ± 19.93 81.79 ± 10.21 19.83 ± 7.23 21. 09 ± 6.60 19.03 ± 5.53 18.74 ± 2.70 14.85 ± 3.39 13.35 ± 2.23 17.90 ± 5.20 14.87 ± 3.14* 7.33 ± 3.96 7.43 ± 3.13 rs2577074 AA 84.45 ± 19.93 83.16 ± 9.36 19.83 ± 7.23 22.14 ± 5.56 19.03 ± 5.53 19.30 ± 2.79 14.85 ± 3.39 14.11 ± 2.63 17.90 ± 5.20 15.95 ± 4.08 7.33 ± 3.96 6.50 ± 2.66 AG 81.24 ± 20.65 85.75 ± 10.34 20.49 ± 8.02 21.99 ± 6.14 17.76 ± 5.73 19.59 ± 3.34 13.70 ± 3.53 14.51 ± 2.38 16.67 ± 5.22 16.17 ± 3.75 7.58 ± 4.03 7.62 ± 3.05 GG 80.46 ± 18.15 84.48 ± 12.39 20.22 ± 6.60 22.54 ± 6.09 17.02 ± 5.45 20.17 ± 3.62 14.39 ± 2.97 13.63 ± 2.83 16.73 ± 5.62 16.21 ± 3.26 7.44 ± 3.53 7.04 ± 3.41 rs2249810 AA 82.33 ± 21.05 87.79 ± 14.62 18.87 ± 7.51 23.07 ± 6.58 18.80 ± 5.80 21.00 ± 4.28 15.03 ± 3.54 13.86 ± 3.03 17.70 ± 5.55 16.57 ± 3.82 6.80 ± 3.89 6.71 ± 3.43 AG 81.67 ± 20.87 85.00 ± 10.52 20.46 ± 8.01 21.97 ± 6.19 17.85 ± 5.84 19.60 ± 3.03 13.66 ± 3.57 14.38 ± 2.53 16.88 ± 5.35 16.29 ± 3.54 7.68 ± 4.05 7.32 ± 3.19 GG 81.77 ± 17.73 83.92 ± 9.27 20.74 ± 6.54 21.90 ± 5.56 17.42 ± 5.20 19.27 ± 3.12 14.42 ± 2.88 14.25 ± 2.48 16.74 ± 5.18 16.05 ± 3.92 7.57 ± 3.61 7.17 ± 2.83 rs2118343 CC 82.74 ± 19.47 85.00 ± 2.00 21.04 ± 7.30 19.33 ± 0.58 17.71 ± 5.57 20.00 ± 3.46 14.38 ± 3.23 13.33 ± 2.52 17.23 ± 5.47 18.33 ± 3.51 7.43 ± 3.93 8.00 ± 4.00 CG 80.05 ± 20.86 85.17 ± 10.43 19.03 ± 7.57 21.90 ± 5.72 17.90 ± 5.77 19.35 ± 3.29 13.63 ± 3.58 13.90 ± 2.41 16.63 ± 5.22 16.53 ± 3.45 7.68 ± 3.84 7.60 ± 3.21 GG 85.43 ± 15.64 84.50 ± 10.63 20.71 ± 8.28 22.32 ± 6.09 20.14 ± 5.18 19.68 ± 3.21 15.71 ± 3.20 14.40 ± 2.61 16.71 ± 4.23 15.86 ± 3.88 6.43 ± 3.82 6.96 ± 2.92 rs6506891 AA 81.07 ± 20.23 84.08 ± 9.28 18.48 ± 7.34 22.06 ± 5.66 18.55 ± 5.74 19.31 ± 3.11 15.14 ± 3.55 14.27 ± 2.46 17.55 ± 5.59 15.95 ± 3.97 6.41 ± 3.33 7.17 ± 2.81 AT 79.48 ± 20.69 84.84 ± 10.51 19.08 ± 7.65 21.93 ± 6.14 17.69 ± 5.61 19.63 ± 3.01 13.29 ± 3.56 14.34 ± 2.53 16.31 ± 4.84 16.20 ± 3.58 7.85 ± 3.92 7.32 ± 3.17 TT 82.94 ± 19.02 86.87 ± 14.53 21.39 ± 7.24 23.20 ± 6.36 17.68 ± 5.60 20.67 ± 4.32 14.32 ± 3.15 13.67 ± 3.02 17.10 ± 5.49 16.40 ± 3.74 7.52 ± 3.86 6.53 ± 3.38 * P < 0.05, compared with each other genotype, LSD tests Combine stage 1 and 2 samples: rs2118343 genotypes were significantly associated with negative factor scores Yang et al. Behav Brain Funct (2018) 14:1 Page 6 of 7 Abbreviations [17] in the serotoninergic system and Glutamate iono- SZ: schizophrenia; CDNF: cerebral dopamine neurotrophic factor; BDNF: brain- tropic receptor NMDA type subunit 2B [16] and Reelin derived neurotrophic factor; PD: Parkinson’s disease; SNPs: single nucleotide [28] in the glutamatergic system and SZ. The present polymorphisms; DSM-IV: diagnostic and statistical manual of mental disorders fourth edition; OR: odds ratio; 95% CI: 95% confidence intervals; LD: linkage study focused on CDNF2 because of its role in the dopa- disequilibrium; ANOVA: analysis of variance; PANSS: positive and negative minergic system. Our results from two sets of samples symptom scale. suggest that SNP rs2249810 of CDNF2 may be a sus- Authors’ contributions ceptibility locus for SZ and provide evidence that it is LL and JT participated in the design of the study and made final approval caused by the interaction of a large number of suscepti- of the version to be published. YY, WL and BL were involved in drafting the bility genes [29]. To date, there has been a lot of GWAS manuscript and data analysis. WL, YY, and HZ carried out the molecular genetic examination. YY, HY, SD and YL conducted sample selection and data researches on the susceptibility site of SZ [7–11, 30], and management. All authors read and approved the final manuscript. a recent meta-analysis using GWAS data also found 30 new sites [31]. However, there is still no reported asso- Author details Key Laboratory for NeuroInformation of Ministry of Education, School of Life ciation between CDNF2 and SZ. The difference between Science and Technology, University of Electronic Science and Technology GWAS and our research is samples selected more than of China, Chengdu, China. Department of Psychiatry, Henan Mental Hospital, three groups and multi-ethnic in the former, one group The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. Henan Key Lab of Biological Psychiatry, Xinxiang Medical University, Xinxiang, and only Han Chinese people in the latter. Therefore, our China. Brainnetome Center, Institute of Automation, Chinese Academy of Sci- sample has a single genetic background. Meanwhile, we ences, Beijing 100190, China. National Laboratory of Pattern Recognition, found rs2577075 genotypes and haplotype TGATC may Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China. The Queensland Brain Institute, University of Queensland, Brisbane, QLD be susceptibility factors of SZ in stage 2 samples, but 4072, Australia. Department of Psychiatry of the Second Affiliated Hospital those results were not found in total samples. That may of Xinxiang Medical University, No. 388, Jianshe Middle Road, Xinxiang 453002, be the majority of the samples were paranoid, and with China. less undifferentiated in total samples. Therefore, those Acknowledgements results need to be further validated in a large sample, The authors thank the patient, their families, and the healthy volunteers for especially in the samples with multiple subtypes of SZ. their participation, and the physicians who collect clinical data and blood samples in the Second Affiliated Hospital of Xinxiang Medical University. SZ is characterized by positive and negative symptoms, cognitive deficits, and disorganization of thoughts and Competing interests behaviors [32, 33]. SZ is considered a dopamine disorder The authors declare that they have no competing interests. based on the psychosis-inducing effects of dopamine- Availability of data and materials releasing drugs such as amphetamines, and the anti- The datasets used and/or analysed during the current study are available from psychotic effects of drugs that block the dopamine D2 the corresponding author on reasonable request. receptor [34]. Dopamine dysfunction has been identified Consent for publication as the major cause of SZ [35]. Our results have shown Not applicable. that CDNF2 gene polymorphisms underlie the manifes- Ethics approval and consent to participate tations of SZ symptoms; moreover, rs2118343 genotypes The study protocol was in accordance with principles of the Declaration of were associated with negative factor subscores in SZ Helsinki and approved by the Ethics Committee of the Second Affiliated Hos- patients; this provides the first evidence of an associa - pital of Xinxiang Medical University. Written, informed consent obtained from each participant after they were informed of the purpose and procedures tion between CDNF2 and negative symptoms in SZ and of the study. All authors had no access to information that could identify is consistent with our previous observations of a genetic individual participants during or after data collection. basis for SZ symptoms [16, 17, 28]. Funding This study had some limitations. Firstly, our sample size This work was supported by the National Natural Science Foundation of China was not large enough to obtain complete PANSS scores. (81371472 and U1404811), the National Key Basic Research and Development Secondly, although we validated our results in two inde- Program (973) (Grant 2011CB707800), the Medical Science and Technology Foundation of Henan Province (201702131), the Open Project Program of the pendent datasets, undifferentiated subtypes were only National Laboratory of Pattern Recognition (NLPR) (201600010). included in the stage 2 analysis. Publisher’s Note Conclusion Springer Nature remains neutral with regard to jurisdictional claims in pub- In summary, our findings suggest that SNP rs2249810 of lished maps and institutional affiliations. CDNF2 is a novel susceptibility locus in SZ. 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Journal
Behavioral and Brain Functions – Springer Journals
Published: Dec 1, 2018
Keywords: neurosciences; neurology; behavioral therapy; psychiatry