**3.4 ERPs and paradigms**

We detected large discrepancies between the ERP procedures used across the studies. EEG acquisition and ERP preprocessing protocols varied widely in terms of *OXTR Gene Polymorphisms and Event-Related Potentials in Humans: A Systematic Review DOI: http://dx.doi.org/10.5772/intechopen.112631*

**Figure 2.**

*Report of genotypic frequencies for rs53576 polymorphism in each study. GG = carriers of the GG genotype; GA = carriers of the GG genotype; AA = carriers of the AA genotype. \*Studies that did not satisfy the HWE.*

sensor number (**Table 1**), referencing, filtering, artifact detection, artifact correction, and epochs selection. For example, the four studies that ran algorithms to correct artifacts did not justify their decision. EPR construction was also heterogeneous across the reports. Indeed, the reports generally provided little justification about the procedures that led to electrode number reduction, selection of latency ranges, and potential measurements. Most authors remarked that they selected latency ranges by means of visual inspection of the grand average waveform, and even one study specified a range for each participant [16]. Therefore, latencies for each family of components varied greatly (see component lines in **Figure 3**). Regarding the ERP measures, four studies calculated the latency peak and the amplitude peak for each latency period [16, 17, 19, 22], while the other four studies used the amplitude average for each latency window [18, 20, 21, 23]. All paradigms were time-locked with the stimuli, meaning no paradigm was time-locked with the responses. All studies employed visual affective or visual social stimuli; four used faces, two used affective images, and two used pictures of people suffering (**Table 1**).

### **3.5 Main findings**

**Figure 3** summarizes the ERP component amplitude differences between OXTR rs53576 genotypic groups, as reported by the reviewed studies. On the one hand, OXTR genotypes were not significantly associated with the P1 or the N170 components during the socio-affective tasks. Similarly, neuronal responses occurring after 600 ms were not explained by any genetic variation of the OXTR. On the other hand, the studies together found the N1, P2, N2, P3 and LPP potentials to have a significantly higher amplitude in GG carriers during the experimental tasks. Such genotypedependent components can be grouped into three general time ranges of the neural dynamics (colored heads in **Figure 3**). The earliest differences in neural activity were found between 50 and 200 ms in centro-parietal and frontal zones (respectively N1 and P2; blue head). The OXTR also affected middle neural processing in the latency

#### **Figure 3.**

*Differences in ERP components across carriers of distinct OXTR rs53576 polymorphisms. At the top, the heads display the brain regions where components were recorded. Their colors represent a family component: blue = early, red = middle, and orange = late. At the bottom, the leftmost column contains the studied components. The middle column shows latencies in milliseconds, where lines represent the components examined in their respective paper and their lengths indicate the latency range used to calculate the component. Black dotted lines represent nonsignificant differences between genotypes, whereas colored solid lines point out significant differences. Doble lines indicate a higher component amplitude in GG carriers, while single lines denote a higher component amplitude in A-allele carriers. The rightmost column shows the source study.*

range between 200 to 350 ms in posterior regions, specifically, the EPN component (red head). The last differences in neural activity were observed in the central regions of both frontal and parietal lobes in latencies between 300 and 500 ms (P3 and LPP; orange head).

Face processing was generally not different across OXTR genotypes. Specifically, amplitudes of neural responses to upright or inverted faces did not vary significantly in healthy adults [19], mothers [22], children [17], or autistic children [16]. However, a significant interaction was observed in the N1 latency. Peltola's team found that, unlike A carriers, GG carriers had a shorter N1 latency to strong-intensity infant faces than they had to mild-intensity ones [22]. Likewise, Munk et al. [19] found a significant interaction in the N170 latency, where A-allele carriers had shorter latencies in the right hemisphere in reaction to upright angry faces. Nevertheless, such a difference was not observed in a replication sample [19].

The processing of affective images varied in function of the rs53576 genotypes. GG homozygotes exhibited a more negative posterior N1 (50–200 ms) during the perception of affective images of humans and objects and a more negative posterior N2 (200–320 ms) when they perceived affective images of humans only [18]. In the same study, no effects of OXTR genotypes on LPP (600–1000 ms) were found. However, Fowler and colleagues found independently that GG participants responded with a higher parietal LPP amplitude (at 300–500 ms) during the perception of aversive pictures. That said, it should be noted that the LPP latencies and regions of interest

*OXTR Gene Polymorphisms and Event-Related Potentials in Humans: A Systematic Review DOI: http://dx.doi.org/10.5772/intechopen.112631*

were considerably different between the two studies, making it difficult to compare the results (**Figure 3**).

Neural responses to the suffering of others were significantly mediated by OXTR genotypes. Specifically, GG carriers exhibited a heightened frontal P2 amplitude (at 136–176 ms) when they were shown painful expressions adopted by people that the participants perceived as themselves [21]. Additionally, in a previous study [20], frontal P3 was found to be more positive for sadistic painful stimuli in the GG group, which may indicate a bigger excitatory activity in the amygdala and insula.

#### **4. Discussion**

#### **4.1 OXTR polymorphisms and neural processing**

Our results provide evidence that variations in the OXTR gene are associated with differences in brain activity during socioemotional tasks (**Table 1**). These differences were distributed along several time intervals and brain regions (**Figure 3**). In particular, the main differences were found in rs53576 GG homozygotes, who produce wider neural potentials in the face of salient social stimuli such as people expressing pain.

GG homozygotes exhibited more negative early activity (N1) in posterior cerebral regions when they perceived socially salient cues (**Figure 3**). Psychophysiological studies have previously linked enhancement of the posterior N1 with an attentional shift to prominent stimuli and implicit visual discrimination [24, 25]. Therefore, GG carriers may detect and recognize socio-affective signals more readily. This enhanced activity may originate in interneurons in the occipital, parietal, and temporal areas implicated in social perception. Additionally, it is possible that these areas are excited by afferences from projection neurons in the limbic area, which is rich in OXTRs.

GG homozygotes also had stronger early anterior positive potentials (P2) when they watched people suffering (**Figure 3**). This early frontal excitation may be associated with the involuntary allocation of attentional resources to the processing of the highly arousing images [26, 27], suggesting GG carriers may bear neural mechanisms that enable them to have a more sensitive perception of emotional signals from others.

Moreover, OXTR SNPs produced variations in the N2-EPN potentials in posterior brain regions, with GG homozygotes having wider negative potentials to affective human pictures and AG-AA carriers doing so to affective pictures without humans (**Figure 3**). The N2-EPN component is a typical index of attentional engagement to emotional pictures [28, 29]. It may be generated from interneuron activity in brain regions such as the amygdala, the hippocampus, and the superior and inferior parietal lobes [30, 31], which contain an abundance of OXTRs [32, 33]. Therefore, it seems that OXTR rs53766 polymorphisms influence the activity of posterior corticolimbic networks, which enhances GG carriers' and AA-AG carriers' discrimination and categorization of social cues and nonsocial arousing stimuli, respectively.

The late components modulated by the OXTR rs53576 polymorphisms were positive potentials at frontal (P3; **Figure 3**) and parietal sites (LPP; **Figure 3**). Both ERP components were higher in GG carriers when they perceived pain faces and aversive pictures. The P3 is usually interpreted as an indicator of effortful decisionmaking during demanding tasks [34, 35], as was the case in Luo's experiment [20]. The LPP component is elicited by highly arousing stimuli and has been associated with enhanced memory encoding, appraisal, and suppression of response to affective pictures [36, 37]. These findings may indicate that GG homozygotes' greater

sensitivity to social images allows them to execute enhanced top-down processes to evaluate arousing social contexts and to control their responses in accordance with such contexts. However, these interpretations are necessarily preliminary, considering that six of the reviewed studies failed to find any significant differences in the LPP component between OXTR genotypes.

Overall, these findings are consistent with the social salience hypothesis, which contends that an increase in oxytocinergic neurotransmission influence neural activity in such a way that the processing of social information is enhanced [38, 39]. Animal research has proven that SNPs in the noncoding region of the OXTR gene have an impact on the number of OXTR receptors in brain regions implicated in social behaviors [40]. Likewise, neuroimage studies have confirmed that OXTR SNPs are associated with variations in brain activity in areas responsible for the processing of social information [8, 41]. In brief, GG homozygotes for the rs53576 SNP may have a higher density of receptors in specific critical areas, which may enhance oxytocinergic neurotransmission in neural networks implicated in the processing of social cues [40].

The null results on the face-specific N170 component are surprising because there exists a long-standing theoretical association between oxytocinergic neurotransmission and face processing [42]. Indeed, Skuse et al. found a link between the OXTR rs237887 alleles and face recognition in families with autistic children [43]. Moreover, fMRi studies have also found significant effects on face recognition involving OXTR SNPs. For example, the Westberg team reported that rs7632287 genotypes differ in recognition of faces and amygdala activity [44]. Similarly, O'Connell and coworkers linked the rs2268498 SNP with inferior occipital gyrus activity due to perception of fear expressions [45]. Nevertheless, these results should be analyzed cautiously given that the Skuke study used a very particular sample and the fMRi studies used tasks sensitive to other psychological functions such as emotional processing and mental inference. What is more, the lack of association between OXTR SNPs and the N170 component, is in line with the nonsignificant relationship between many OXTR SNPs and several face recognition tasks, which was found in an exhaustive study by [46]. Therefore, this evidence together seems to indicate that oxytocinergic neurotransmission is not essential to the early stages of discrimination of facial configurations.

Furthermore, these results could help to understand the conflicting findings on the relationship between genetic variations in the oxytocinergic system and human psychological phenotypes [10]. Variations between genotypes in neural processing during exposure to social cues with high emotional content observed during intermediate and late latencies (100–600 ms) indicate that the oxytocinergic system is central in facilitating the implicit processing of emotional signs during social interactions. Still, this system would have a less relevant and direct role in the awareness of one's affective states; therefore, a minimal effect could be expected when self-report questionnaires or verbal responses are used. In this sense, future studies would benefit from using experimental tasks instead of questionnaires and psychological tests to assess social and emotional phenotypes.

#### **4.2 OXTR polymorphism, neural functioning, and human development**

OXTR polymorphisms influence brain development by modulating the density of OXTRs, by modifying the sensibility toward the social environment, and by orchestrating fine-tuned social transactions during critical periods of brain maturation. Consequently, OXTR rs53576 GG individuals tend to be more sensitive to their social environment, developing larger phenotypic variability [47]. For instance, in

#### *OXTR Gene Polymorphisms and Event-Related Potentials in Humans: A Systematic Review DOI: http://dx.doi.org/10.5772/intechopen.112631*

G allele carriers, protective and synchronic caring favors the development of better emphatic, prosocial, and emotional skills, while childhood adversity leads to more avoidant behaviors and poor social skills. In contrast, A carriers, who are less sensitive, show fewer developmental variations [48, 49]. Moreover, effects of OXTR SNPs on the modulation of developmental plasticity have also been found in neuroimage studies, where limbic and frontal networks have been shown to be more plastic [8, 50, 51]. Plasticity in fronto-limbic networks is consistent with the differences in the ERP components observed in this review.

The developmental plasticity associated with some OXTR genotypes may be due to epigenetic mechanisms. Indeed, numerous studies have reported an association between OXTR DNA methylation and differences in social cognition, emotional behaviors, and neuroendocrine functioning in several moments of human and animal development [52–55]. A recent systematic review found that an increase in OXTR gene methylation was linked with a reduction in receptor expression, social sensitivity, and developmental plasticity, leading to poor social skills and affective dysregulation in healthy and psychopathologic samples [56]. A leading hypothesized mechanism is that people with more G alleles have more CpG islands, facilitating epigenetic modulation and major developmental plasticity, with early adverse experiences as the main predictor of OXTR hypermethylation.

#### **4.3 OXTR polymorphism, neural functioning, and cultural differences**

**Figure 2** shows a large variation in the allelic frequencies of the OXTR rs53576 SNP between Caucasian and Asian samples, which is in line with previous findings that Asian populations have higher A-allele frequencies [57]. This geographic distribution of OXTR genotypes is associated with cultural patterns, including collectivistic values, control of emotional expressions, emotional support seeking, social interdependence, empathy for pain, altruism motivation, prevalence of depression, and brain functioning [58–60]. These cultural and genetic differences may have been shaped in human societies throughout history. Selection for A alleles in collectivistic nations could be the result of son favoritism, prolonged infanticide, and marriage patterns, whereas G allele accumulation may have been facilitated by mothers' investment in childcare and male cooperation in everyday life activities.

These cultural and demographic factors should be considered to better interpret neural functioning differences. In the first place, genotypic frequencies may limit statistical analysis. For example, since Caucasian samples have fewer AA carriers, such studies require larger samples to find significant results. Further, as cultural values and relational tendencies have important effects on various genotypes, it is indispensable to include measures for these variables. Finally, samples that do not satisfy the HWE must be carefully analyzed because the sampling could be biased, or evolutionary pressures could be affecting the genetics of these populations [61].

#### **4.4 Limitations and future directions**

#### *4.4.1 Samples*

Three important sample issues can be identified. First, no studies included participants from South America, Central America, Africa, Eastern Europe, the Middle East, or Oceania. There exist important variations in the allelic frequencies between these regions, which may be related to differences in behavior and brain

function. Therefore, generalization of these results to diverse geographic and cultural regions is limited, such as in Conner et al. [10] report, who did not find an association between OXTR rs53576 SNP and emotional trait, but they only included a sample from New Zealand. Second, studies have focused on young adults, and there are no inquiries on infants, adolescents, or elderly. Since adolescence is considered a sensitive period for developing social skills [62], the lack of studies at this age range restricts our understanding of how OXTR polymorphisms influence the development of brain activity and social behavior from childhood to adulthood. There is evidence that during adolescence OXTR polymorphisms produce high social sensitivity, opening a critical period to rewiring brain networks and reorganizing behavior, as the oxytocin system interacts with pubertal hormones to create age- and sex-dependent developmental trajectories [63]. And third, the small sample sizes used in the studies limit the possibility of finding significant results. Guidelines to ERPs recommend including over 40 participants per condition [64], meaning researchers may need to incorporate samples of more than 120 participants to analyze the effect of variables such as sex, age, and other polymorphisms. Finally, larger samples are necessary to get lower p-values and more marked effect sizes, which are ideal conditions to reproduce results and consolidate this scientific field, although if large samples of different populations and cultural contexts are included, so much genetic and phenotypic variation can be added that it can be challenging to get satisfactory results.
