Social pain refers to the hurt feelings caused by rejection or ostracism from the group. These aversive social experiences

generally cause negative emotions and result in a loss of sense of belonging, control, and self-esteem (Williams, 2009). Some studies have found a role for the dorsal anterior cingulated cortex (dACC) and the right VLPFC in experienced and observed social exclusion conditions, suggesting the presence of a partially overlapping neural network involved both in physical and social pain (Eisenberger et al., 2003; Kross et al., 2007; Wager et al., 2008; Masten et al., 2009). The right VLPFC, in addition to being broadly involved in emotion regulation, has also been found to have a crucial role also in regulating the pain associated with social exclusion (Onoda et al., 2010).

These findings have lead researchers to test the effects of tDCS over brain regions involved in social pain regulation, mainly the right VLPFC. For example, participants in a study by Riva et al. (2012) received 15 min of anodal tDCS over the right VLPFC. At the end of the stimulation, participants were randomly assigned to be included or excluded in a virtual ball-tossing game called Cyberball (Williams et al., 2000). In the inclusion condition, subjects received a ball the same number of times as the other two players, whereas in the exclusion condition participants received the ball only on the first throws. Actually, participants did not play with real players; a computer program controlled the ball. Results revealed that anodal tDCS over right VLPFC, compared to sham stimulation, reduced levels of pain and hurt feelings among excluded subjects.

In a similar study, the same research group (Riva et al., 2014a) tasted the effects of tDCS on behavioral aggression following social inclusion or exclusion condition in the Cyberball paradigm. Participants received anodal or sham stimulation during the Cyberball game. At the end of the stimulation, subjects had to choose the amount of hot sauce for their ostensible partners to taste. This is the well-validated hot-sauce paradigm for studying aggression (e.g., Lieberman et al., 1999). Findings indicated that increasing right VLPFC cortical activity with tDCS reduced behavioral aggression among excluded participants, who were no more aggressive than included ones. These findings were replicated in a subsequent study (Riva et al., 2017), which found that brain polarization through anodal tDCS over the right VLPFC reduced unprovoked aggression as measured by the Taylor aggression paradigm (Taylor, 1967).

Similar results were obtained by Kelley et al. (2015a), who also paired a Cyberball game with prefrontal tDCS. In this modified version of the game, participants first chose a partner from a group of images of eight opposite-sex individuals. A third Cyberball player was assigned by the experimenter and was always the same sex as the participant. Harmon-Jones et al. (2009) had found that this Cyberball game evokes jealousy and that self-reported jealousy after being excluded by a desired partner correlates with relative left frontal cortical activity. Kelley et al. had participants choose a partner in the modified Cyberball paradigm and play a practice version of the game before receiving 15 min of tDCS in one of three conditions: excitatory left DLPFC stimulation (anode over F3/cathode over the F4), excitatory right DLPFC stimulation (cathode over F3/anode over F4), or sham stimulation. Stimulation to increase relative left frontal cortical activity increased self-reported jealousy. Because the direct manipulation of cortical excitability with tDCS produced the same outcome as the correlational finding reported Harmon-Jones et al. (2009), this study suggests that tDCS over the dorsolateral prefrontal cortex does indeed modulate emotive responses associated with social exclusion and asymmetric frontal cortical activity.

Collectively, these studies highlight the effects of tDCS over the prefrontal cortex on regulating responses to social exclusion. This work may have clinical implications for disorders characterized by maladaptive responses to social exclusion (e.g., borderline personality disorder). Future research should test the extent to which the increased negative affect and autonomic arousal (Kopala-Sibley et al., 2012) and inappropriate coping strategies and impulsive behaviors (Dixon-Gordon et al., 2011; Coifman et al., 2012) associated with these disorders can be modified by tDCS.

#### Empathy

Recently, some research has observed that personal physical suffering and empathy for the pain of others share the same neural network, involving prefrontal cortex as well as somatosensory cortex, anterior cingulate cortex, amygdala, and anterior insula (Eisenberger, 2012). To investigate the role of prefrontal cortex in empathic pain regulation, Boggio et al. (2009) conducted a study in which participants judged the unpleasantness of pictures showing human beings under painful conditions. Anodal tDCS was applied over the left DLPFC, the primary motor cortex, and the primary visual cortex (control site) in three experimental sessions. Findings revealed decreased unpleasantness and discomfort during anodal stimulation over left DLPFC compared to sham stimulation. Moreover, compared to a previous study in which tDCS was delivered together with an electrical peripheral stimulation (Boggio et al., 2008), no significant effects were found in the primary motor cortex stimulation condition, suggesting that DLPFC specifically contributes to the emotional processing of empathic pain.

These findings were expanded by a similar study comparing emotional reactions to negative, positive, and neutral human pictures (Peña-Gómez et al., 2011). This study found that anodal tDCS over the left DLPFC reduces only painful and not positive or neutral affects. Based on previously mentioned neural models (Phillips, 2003; Phillips et al., 2008; Kohn et al., 2014) and previous neuroimaging evidences regarding DLPFC involvement in more cognitive forms of emotion regulation (Blair et al., 2007; Boggio et al., 2007a; Ochsner et al., 2009; Peña-Gómez et al., 2012), the authors suggested that increasing activity in the DLPFC may enhance cognitive control of emotional reactions. Moreover, the tDCS effect was more noticeable for participants with higher subclinical scores on the introversion personality dimension, perhaps due to their enhanced ability to control emotion expression, which correlates with the increased cortical activity, compared with extraverts, especially in the frontal lobes (Suslow et al., 2010).

A similar finding was reported also by Feeser et al. (2014), who applied anodal tDCS over the right DLPFC while participants applied cognitive reappraisal strategies to downor up-regulate the emotions elicited by negative or neutral pictures. Skin conductance responses were also assessed. Anodal

tDCS, compared to sham stimulation, increased emotional and autonomic reactions when the reappraisal instruction was to upregulate emotions and decreased emotional and autonomic responses when participants attempted down-regulation. Taken together, the studies reviewed here implicate DLPFC and VLPFC in emotion regulation when observing or experiencing painful situations, thereby highlighting the feasibility of tDCS application for the study of pain and empathy for pain.

#### Risk Taking

In addition to emotion and mood manipulations, another way researchers have explored the consequences of prefrontal brain stimulation on emotion regulation is by studying risk taking. Risk taking involves the possibility of punishment or potential harm in the pursuit of rewards or goal-relevant actions. From an emotion-regulation perspective, risk-taking involves managing the emotions associated with the anticipation of winning and losing. In a seminal tDCS study, Fecteau et al. (2007a) used tDCS over the DLPFC during a risk task (Rogers et al., 1999). Across 100 trials of a gambling task, participants viewed 6 horizontal boxes. Some boxes were blue, and some were pink, and the ratio of blue to pink boxes varied from trial to trial. The ratio could be 5:1, 4:2, or 3:3. Of the two options, the high likelihood option was always associated with a small reward whereas the low likelihood option was always associated with a large reward. Participants were to indicate which color box contained a token. Each trial selecting the winning color box earned a reward but selecting the incorrect color box incurred a penalty. Larger rewards were always paired with riskier decisions such that correctly choosing a pink box with a low win probability (1/6) would result in a large reward whereas making that same choice and losing was associated with same magnitude of a loss. Thus, participant's tendency to choose high-risk/unlikely rewards over low risk/likely rewards was the measure of risk-taking. Results indicated that excitatory right DLPFC stimulation increased the number of participants earned by decreasing risk taking on the task. These results suggest that excitatory stimulation over the right DLPFC tilted participants toward safer, less risky choices, as though they were less tempted by the larger, riskier rewards.

These findings have been partially replicated by Cheng and Lee (2016), who found that the excitatory stimulation over the right DLPFC influences performance on the Risky Gains Task (RGT; Paulus et al., 2003), but not on the Balloon Analogue Risk Task (BART; Lejuez et al., 2002). Regarding the RGT task, participant's goal was to win as many points as possible. To accomplish this goal, they made quick (1 s) decisions between taking a reward (i.e., points) now or waiting for a larger point value later. However, this later-but-larger reward also came with the risk of being punished (i.e., losing points equivalent to the later-butlarger reward). Risk-taking was quantified as the rate at which participants selected trials for which punishment was possible whereas safe decision-making was the rate at which participants chose point values with no possibility of punishment. The effect of excitatory right DLPFC stimulation on risky (but not safe) trials was moderated by individual differences in impulsivity, such that greater risk-taking was associated with greater (versus lower) impulsivity. More recently these results have recently been conceptually replicated in a clinically impulsive sample. Gilmore et al. (2017) paired excitatory stimulation over the right DLPFC (twice a day for 5 days) with a balloon analog risk taking (BART) task. They found that excitatory stimulation over the right DLPC reduced risk-taking by 46%. This diminished risk-taking persisted at a two-month follow-up.

Another study probed the underlying neurocircuitry that may be driving the changes in risk taking. Weber et al. (2014) used excitatory stimulation over the right DLPFC, prior to functional MRI during which participants completed the BART. They found that excitatory stimulation over the right DLPFC increased activity in the right DLPFC and the ACC as well. Additionally, this pattern of stimulation also influenced how these two regions connected with the rest of the brain. Specifically, greater right DLPFC-whole brain connectivity was associated with diminished risk-taking on the BART. These results suggest that the diminished risk-taking linked to excitatory right DLPF stimulation influences the neurocircuitry implicated in successful self-regulation.

In addition to laboratory risk-taking paradigms, an innovative study paired prefrontal tDCS with a more ecologically valid form of risk taking: driving behavior. In a driving simulator study, Beeli et al. (2008) observed that excitatory stimulation of the DLPFC (either left or right) led participants to keep a safer distance behind a lead driver and reduced the number of speeding errors. This pattern of stimulation did not influence average speed or revolutions per minute. These results are broadly consistent with reduced risk taking, but they differ from the risk-taking findings reviewed above in a crucial way: the electrode montage used. Whereas the risk-taking studies described above paired excitatory stimulation over the right DLPFC with inhibitory stimulation over the left DLPFC, the study be Beeli and colleagues placed the cathode over the ipsilateral mastoid. Because of this difference in electrode montages it is unclear to what extent these results are comparable to the risk-taking studies above. Future studies should explore the extent to which anodal right DLPFC/cathodal left DLPFC stimulation influences risk-taking in this domain.

In summary, numerous studies have observed enhanced self-regulation after anodal tDCS over right DLPFC (cathodal over left). Improved self-regulation manifested in a variety of ways including greater pain tolerance, healthier food choices, less impulsive decision-making, improved emotion regulation, reduced anger and aggression, less sadness and fear, more empathy, and less risk taking. Collectively, these results anodal tDCS over right DLPFC may be one tool that shows promise in helping individuals live happier, healthier lives.

#### Limitations and Future Directions

We have reviewed evidence suggesting that non-invasive brain stimulation over the prefrontal cortex may improve human selfregulation. First, we detailed a methodological review of tDCS highlighting that tDCS is a safe, inexpensive, and easy to use technique that can be used to study higher-order cognition, emotion, and clinical phenomena. We also reviewed stimulation parameters that may help or hinder tDCS efficacy including current density, stimulation duration, and the orientation and focality of the electrical field. Second, we reviewed findings

from experiments observing that non-invasive brain stimulation over the PFC can enhance three paradigmatic forms of selfregulation: persistence, delay behavior, and impulse control. Although the current review focused predominantly on tDCS, other techniques such as low energy neurofeedback (e.g., Ochs, 2006) and transcranial ultrasound (e.g., Tufail et al., 2011) also represent low-cost, non-invasive techniques for investigating the causal role of neural activation in various forms of self-regulation.

Although much of this review highlighted the ability of brain stimulation to promote self-regulation, under the right circumstances brain stimulation may also undermine selfregulation. For example, we highlighted studies wherein excitatory stimulation over the right DLPFC enhances inhibition (e.g., Kelley and Schmeichel, 2016) whereas excitatory stimulation over the left DLPFC increases approach motivated negative emotions like anger (e.g., Hortensius et al., 2012) and jealousy (e.g., Kelley et al., 2015a,b). These contrasting findings imply that excitatory tDCS is not an unmitigated good that improves self-regulation in all cases. In fact, these findings emphasize the need to identify precise stimulation parameters that help versus hinder self-regulation. Below, we discuss inconsistencies, unresolved questions, and new directions emanating from the above review.

#### tDCS Dosage

The efficacy of eliciting changes in brain activity using tDCS depends on several physical parameters including current density, stimulation duration, and the orientation and focality of the electrical field. These parameters constitute the tDCS dosage. As we noted above, different electrode positions modulate different neuronal groups and elicit different evoked potentials in the case of primary motor cortex and primary visual cortex stimulation, respectively (Priori et al., 1998; Antal et al., 2004; Accornero et al., 2007), and these different electrode positions may also determine effects on the targeted brain region due to electrical field interactions associated with neuronal geometry (Nitsche and Paulus, 2000; Nitsche et al., 2008).

Whereas the coupling of anodal-excitatory and cathodalinhibitory effects is well established in the sensorimotor domain, the evidence pertaining to higher cognitive functions is more controversial (Jacobson et al., 2012). Indeed, when dealing with more complex functions represented by large and interconnected neural networks comprising both excitatory and inhibitory connections, it is more difficult to obtain predictable outcomes – especially when different electrode montages have been used across studies. Hence it is not always the case that anodal tDCS leads to an enhancement (e.g., better performance in a task) and cathodal tDCS leads to a diminution of the assessed cognitive function (Fertonani and Miniussi, 2017).

To illustrate this point, consider the studies above on physical pain tolerance. These studies found increased pain tolerance as the result of excitatory stimulation of the right DLPFC (Mylius et al., 2012), excitatory stimulation over the left DLPFC (Boggio et al., 2008; Mariano et al., 2016), and inhibitory stimulation over the left DLPFC (Powers et al., 2018). Of the four studies we reviewed, three difference electrode montages were used. Notably, the study by Powers and colleagues, unlike the other pain studies, paired tDCS with clinical interventions. These methodological differences likely contributed to the differences in results across studies and thus makes interpreting the effects of tDCS difficult. Future studies should more precisely optimize the stimulation protocols that accentuate versus undermine selfregulation for easier comparison across studies.

More broadly, however, the findings from the pain studies are congruent with the findings from studies of other selfregulatory domains in suggesting that stimulation over right DLPFC facilitates self-regulation. Whether such stimulation is most profitably paired with inhibitory (cathodal) stimulation over left DLPFC remains to be seen. And the effects of excitatory (anodal) stimulation over left DLPFC on self-regulation are even more uncertain, with some studies finding better and some finding worse self-regulation after excitatory stimulation over left DLPFC.

#### Individual Differences

Another inconsistency in past research concerns individual differences. Despite seminal work suggesting that participants should be matched on individual differences like sex or age that can influence tDCS efficacy (Pitcher et al., 2003; Kuo et al., 2006; Quartarone et al., 2007; Chaieb et al., 2008; Nitsche et al., 2008), many of the studies reviewed above did not use this strategy, and we recommend future studies implement matching procedures to reduce error variance and increase power to detect tDCS effects.

In addition to demographic factors, which may subtly influence tDCS efficacy, many of the studies we reviewed also did not consider the extent to which participants are responsive to tDCS. Previous research has found that between 50 and 64 percent of participants are responsive to tDCS protocols, which leaves a substantial proportion of individuals who are not particularly responsive to tDCS (Wiethoff et al., 2014; López-Alonso et al., 2015). Studies that include non-responders and studies that do not systematically test for differences between responders and non-responders many obscure effects of tDCS on regulatory behavior. Further, only few studies have considered individual differences traits, though these are also likely to moderate tDCS effects. For example, the study by Kekic et al. (2014) found that tDCS-driven reductions in food craving were more pronounced among participants with low (versus high) delay discounting tendencies. Evidence of this sort highlights the need to develop more robust stimulation protocols in wellpowered studies that can systematically test for the moderating role of individual differences.

#### Impulse-Behavior Relationship

Another inconsistency in the research reviewed above concerns whether changes in emotive responding extend to changes in behavior. We summarized evidence that tDCS may alter food craving without altering food consumption (although sometime consumption changes, too; e.g., Fregni et al., 2008). Similarly, we summarized evidence that changes in emotional responses (e.g., anger) may occur in both the absence of and presence of corresponding changes in behavior.

The path from impulse to behavior entails multiple determinants, and thus impulses and behaviors may diverge for

several reasons. Practical considerations including variability in stimulation dosage may explain why tDCS sometimes does and sometimes does not influence behavior. For example, one important aspect of the tDCS dosage is electrode size. The study by Kekic et al. (2014) who did not find effects on food consumption used 25 cm<sup>2</sup> electrodes whereas Fregni et al. (2008) used 35 cm<sup>2</sup> electrodes. Smaller electrodes are more spatially precise compared to larger electrodes. The larger electrodes may affect distal brain regions that are less affected in studies using smaller electrodes possibly accounting for why the study by Fregni et al. founds effects on consumption, but Kekic did not. Beyond these practical considerations idiosyncratic food preferences may have played a role in the inconsistent results. The studies assessing compulsion offered actual food to participants, but those foods were not specifically tailored to the participant. Instead participants were offered foods that are generally (but not universally) well liked, such as chips, cookies, and chocolate. This may be problematic insofar as some participants may not prefer any of the food options offered by the experimenter. Future studies using more ecologically valid measures of food consumption and others types of regulatory behavior (e.g., naturalistic observation) may prove useful in clarifying the extent to which tDCS-induced changes in emotions/impulses influence subsequent behavior. However, we must also consider the possibility that cravings/subjective states are more readily influenced by tDCS, whereas behaviors may be harder to change as they have a multiple of determinates above and beyond the preceding subjective state.

#### How Does tDCS Effect Underlying Brain Activity?

The effects of tDCS on underlying brain activity are not well understood and subject to ongoing debate. It remains to be seen how tDCS affects brain activity and how these changes relate to changes in self-regulation. One way to advance research on this topic is to pair concurrent measures of brain function with electrical stimulation. Candidate neural processes mediating links between tDCS and self-regulation include changes in prefrontal EEG alpha and functional connectivity between the prefrontal cortex and subcortical regions.

#### Prefrontal Alpha

One potential mediator driving many of the effects reported in the current review is EEG alpha activity. Specifically, lateralized patterns of alpha activity may reflect a person's motivational orientation with left lateralized EEG alpha activity reflecting approach-motivation (Tomarken et al., 1992; Harmon-Jones and Allen, 1997, 1998; Sutton and Davidson, 1997; Harmon-Jones and Sigelman, 2001; Harmon-Jones et al., 2002, 2006; Coan and Allen, 2003; Harmon-Jones, 2007) and right lateralized pattern of EEG alpha activity has been linked to withdrawal or avoidance motivation (Davidson et al., 1990; Tomarken et al., 1990; Dawson et al., 1992; Kalin et al., 1998; Coan et al., 2001). Self-regulatory failure tends to occur when individuals have strong impulses such as strong impulses to engage in approach or avoidance motivated behavior. Likewise successful self-regulation tends to occur when impulses are weaker. To the extent that asymmetric patterns of alpha activity in the frontal cortex reflect the strength of appetitive and aversive impulses they may be a good candidate linking tDCS to changes in self-regulation.

Indirect support for the role of EEG alpha activity in tDCS effects comes from parallel findings using EEG and tDCS, respectively, to study the emotion of jealousy. Harmon-Jones et al. (2009) found that feelings of jealousy during a Cyberball game correlate with greater left frontal alpha activity, and Kelley et al. (2015a,b) found the same pattern by manipulating (rather than measuring) brain activity with tDCS. More specifically, Kelley et al. observed that excitatory stimulation of the right DLPFC paired with inhibitory stimulation of the left DLPFC increases feelings of jealousy during a Cyberball game. By finding the congruent effects with both measured and manipulated brain activity, the pair of results together suggest that EEG alpha activity may mediate the link between prefrontal tDCS and behavioral self-regulation.

In an innovative new study, Vöröslakos et al. (2018) developed an intersectional short-pulse (ISP) stimulation paradigm in cadaver and rodent studies. ISP delivers shorts bursts (less than 10 µs) of high intensity stimulation from multiple electrode pairs centered on a stimulation site of interest. ISP thus offers superior spatial focality plus higher current densities (7–9 MA) more easily tolerated than traditional tDCS paradigms (>2 MA), with relatively low charge densities and scalp sensations. Pairing Vöröslakos and colleagues then paired ISP with concurrent EEG measurement and observed that tDCS affects the amplitude of simultaneously recorded EEG alpha waves. This work provides an important example of how technical studies in mouse and cadaver models can be used to improve existing tDCS protocols. Future research should consider implementing innovate stimulation paradigms like ISP to increase the efficacy of existing stimulation paradigms and to trace the neural mediators of tDCS effects.

#### Functional Connectivity

The self-regulation findings we reviewed may also be mediated by frontal cortical-subcortical interactions. Due to its high spatial resolution, functional MRI is perhaps best suited to probe such possibilities. Research along these lines has already begun. Weber et al. (2014) administered excitatory stimulation over the right DLPFC prior to functional MRI of a risk-taking task. They found that excitatory stimulation over the right DLPFC influences how the right DLPFC connects to the rest of the brain. Specifically, stronger right DLPFC-whole brain connectivity and diminished risk-taking emerged in participants who had received excitatory stimulation over the right DLPFC. Although this study did not measure brain function during tDCS, the finding that tDCS administered immediately prior to a risktaking task influences connectivity patterns revealed by fMRI does highlight that stimulation may influence communication among neural networks. Future studies should continue to probe the extent to which prefrontal stimulation influences connectivity to reward-relevant (e.g., ventral striatum) and threat-relevant (e.g., amygdala) subcortical regions.

Potential neural aftereffects of tDCS, such as changes in prefrontal alpha asymmetry or functional connectivity, may mediate the relationship between tDCS and regulatory behavior.

What remains to be established is the extent to which alpha asymmetry or functional connectivity carry the causal effects of tDCS on self-regulation, or whether they merely correlate with observed changes in regulatory behavior.

#### How Do Impulse and Control Strength Contribute to Regulatory Behavior?

Imagine a person who, when offered a chocolate treat, decides not to eat it. Does foregoing chocolate reflect the application of control to resist chocolate consumption, a low desire for chocolate, or some combination of both things? Social psychologists have traditionally viewed self-regulatory success as the consequence of applying self-regulatory strength (see Baumeister et al., 1994, 1998, 2007). In this view, a person forgoes chocolate by resisting the temptation to eat it. But impulse strength also contributes to self-regulatory outcomes. Presumably, weaker impulses are easier to control or hardly require control at all (e.g., Inzlicht and Schmeichel, 2012; Kelley et al., 2018). Successful self-regulation has been associated both with increased activity in areas associated with top-down control, including the prefrontal cortex, and reduced activity in subcortical regions involved in reward and threat processing. These patterns also implicate and potentially confound strong control and weak impulses. Thus, an unresolved issue concerns the relative contribution of control strength and impulse strength to self-regulatory outcomes. By paring tDCS with measures of concurrent brain function, it may be possible to compare the contributions of neural activity caused by (1) stimulation to areas associated with impulse strength, and (2) stimulation to increase activity in control regions.

#### What Are the Long-Term Consequent of Brain Stimulation on Regulatory Behavior?

In addition to limited understanding of the effects of tDCS on underlying neural processes, we also have a limited understanding of the long-term effects of tDCS. Most of the studies we reviewed involved just a single session of tDCS. Although some studies have involved the administration of tDCS once a day for multiple days (Fregni et al., 2006a; Boggio et al., 2007b), those studies have primarily been conducted with patients recovering from spiral cord injury or stroke. Pairing repeated stimulation with measures of self-regulation in nonpatient samples may yield stronger, more consistent effects.

Self-regulation research touches on alcohol and drug addiction, personal debt, obesity, and a variety of other consequential outcomes. It is important to acknowledge that these outcomes are not the result of one decision or behavior but instead results from multiple patterns of behavior unfolding over long periods of time. Few studies have examined long-term

#### REFERENCES

Accornero, N., Li Voti, P., La Riccia, M., and Gregori, B. (2007). Visual evoked potentials modulation during direct current cortical polarization. Exp. Brain Res. 178, 261–266. doi: 10.1007/s00221-006-0733-y

downstream effects of stimulation. One notable exception was a study by Gilmore et al. (2017), who found that excitatory stimulation over the right DLPFC (twice a day for 5 days) reduced risk-taking at the end of the stimulation period and at a two-month follow-up. We encourage future studies to follow the example of Gilmore and colleagues and use both repeated stimulation paradigms and longitudinal designs to examine changes in behavior. Extend this work to include also concurrent changes in brain function would help to more precisely map the long-term consequences of tDCS on regulatory behavior.

### CONCLUSION

Self-regulation is crucial for goal-directed behavior and contributes to many consequential outcomes in life including physical and mental health, decision making, and interpersonal functioning. Likewise, failure at self-regulation is thought to contribute to alcohol and drug addiction, personal debt, obesity, and other outcomes that carry both personal and societal costs. Based on the evidence reviewed here, we conclude that brain stimulation techniques hold promise for improving selfregulation across three broad domains of response: persistence, delay behavior, and impulse control. To maximize the utility of tDCS in future research, we encourage researchers be especially mindful of issues such as dosage and individual differences – issues that have been commonly been neglected in past research and have likely contributed to inconsistencies in past findings. Future research that takes these concerns into account and incorporates concurrent measures of brain activity will bring the promise of tDCS into sharper focus and help to reveal underlying neural mechanisms.

### AUTHOR CONTRIBUTIONS

All authors contributed to the conception, writing, and revising of this manuscript.

## FUNDING

Preparation of this manuscript was supported by National Institute of Health (NIH) grant T32 NS047987 to NK.

### ACKNOWLEDGMENTS

We wish to thank Andrew R. Kittleson and Emily E. Smith for their feedback on previous versions of this manuscript.

transcranial direct current stimulation: direct electrophysiological evidence. Invest. Ophthalmol. Vis. Sci. 45, 702–707. doi: 10.1167/iovs.03-0688

sexual behavior. J. Neurosci. 32, 5549–5552. doi: 10.1523/JNEUROSCI.5958-11. 2012

level of cortical sources: a Reply to Bailey et al., 2015. Cortex 74, 323–328. doi: 10.1016/j.cortex.2015.04.023

development: a 4-year longitudinal study. J. Cogn. Neurosci. 26, 1118–1130. doi: 10.1162/jocn\_a\_00549

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Kelley, Gallucci, Riva, Romero Lauro and Schmeichel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

digital media

of impactful research

article's readership


Conflict of interest

control. These halves were joined, and a fixed number of insects were released on the center. Observations on the number of insects present on both the treated and untreated halves were recorded after 2 and after 4 h. The highest repellent activity

(2 h) and 92% 3 (4 h) were observed, which were higher than those obtained for a commercial repellent at the same concentration and exposure times (78% 5 and

Weevils that consume flour (Tribolium castaneum), peanuts and wheat bread (Ulomoides dermestoides) merit attention alongside other insects of major concern in crop production and storage of cereals and other products. Alcala and co-workers [85] used the area preference method to show that EOs of Elettaria cardamomum, Salvia officinalis and L. origanoides (carvacrol chemotype) had repellent action against both pest insects, while the repellency in the controls was null. This repellency increased when the EO concentrations were higher. None of the EOs

presented attractant action for either of the exposure times. A 100% repellency was obtained at the highest concentration tested (1.6% v/v), except for S. officinalis against U. dermestoides at 2 h of treatment that had a 97% of repellency. Mean repellent concentration (RC50) values showed that E. cardamomum, S. officinalis, and L. origanoides had better repellent properties against U. dermestoides than a commercial preparation that contained 15% of ethyl butylacetylaminopropionate. The carvacrol-rich chemotype of L. origanoides was the most potent, with RC50

Several tropical diseases for which there is no vaccine yet (yellow fever, Zika fever, chikungunya, dengue) are transmitted by Aedes aegypti. The strategies to prevent these illnesses involve the use of insecticide or repellent agents. Since several pesticides have deleterious environmental effects and affect humans, there is a strong interest in finding EOs and plant extracts that can be effective in controlling Aedes aegypti. The guideline that good larvicide candidates are substances with LC50 < 100 mg/L [86] shows the importance of the finding that the EOs from L. origanoides (LC50 = 54 mg/L) and Swinglea glutinosa (LC50 = 66 mg/L) had an improved performance when used as a mixture (LC50 = 38 mg/L). Other EO

values of 0.220 and 0.207% (v/v), for T. castaneum and U. dermestoides,

binary mixtures showed similarly interesting activity (Turnera diffusa and S. glutinosa, LC50 = 64 mg/L; L. alba and S. glutinosa, LC50 = 49 mg/L) [87].

products that employ them as active ingredients.

Colombia's geographic and botanical conditions favor the development of its EOs agroindustry to convert this country into an important provider to the evergrowing EO world market. The initial offer will consist of EOs from aromatic plants of European and Asian origins, which are well-known and commonly traded in the international market. However, the results from the very small survey of Colombia's biodiversity indicate that there are many promising alternatives for future market expansion. The evaluation of biological activities of EOs obtained from plants growing in Colombia points toward many opportunities to develop a wide range of

Financial support from Patrimonio Autónomo, Fondo Nacional de Financiamiento para la Ciencia, Francisco José de Caldas, grants RC-432-2004, RC-0572-2012, and

. Repellence values of 86% 5

was observed at an EO concentration of 0.2 μL/cm2

76% 9, respectively).

Essential Oils - Oils of Nature

respectively.

5. Conclusions

Acknowledgements

138

The authors declare that they do not have conflict of interest.


**1. Introduction**

Solution blow spinning (SBS) is a rising preparation technique to produce polymer films with ultrafine fibers and high specific surface area [1]. A regular SBS apparatus consists of a high velocity air source, a syringe pump, a concentric nozzle system, and a collector [2]. The polymer solution in the inner nozzle is elongated into fine fiber by the surrounding high velocity airflow in the outer nozzle. Moreover, because SBS uses high velocity airflow to form fibers, there is no requirement for the conductivity of the solution compared to electrospinning. As the solvent rapidly evaporates in the process of moving towards the collector, ultrafine fibers deposited and formed a nanofibrous film on the collector [3]. The SBS has served a wide range of purposes that include biosensors, the aerospace industry, impurity removers, and wearable electronics [4]. The development of nanofiber films for food packaging using SBS, however, has undergone little research. For the present, the utilization of nanofiber film in food packaging is primarily manufactured by the electrospinning method [5–9]. Nonetheless, previous works show that the fiber production efficiency of SBS could be much higher than electrospinning. Tandon et al. [10] found that SBS was three times more efficient in fiber production than electrospinning; and

**Citation:** Yang, Z.; Shen, C.; Zou, Y.; Wu, D.; Zhang, H.; Chen, K. Application of Solution Blow Spinning for Rapid Fabrication of Gelatin/Nylon 66 Nanofibrous Film. *Foods* **2021**, *10*, 2339. https://doi.org/ 10.3390/foods10102339

Academic Editor: Christos Ritzoulis

Received: 14 September 2021 Accepted: 28 September 2021 Published: 30 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

in the study of Sett et al. [11], the fiber productivity of SBS was even up to 30 times higher than that of electrospinning. Shen et al. [12] also found that the SBS process could reach a rapid feed rate of 3 mL/h, while the feed rate of the electrospinning is generally between 0.1 mL/h and 0.6 mL/h. In this regard, the SBS technology has demonstrated its promising potential for the fast production of large area nanofiber film for food packaging.

Gelatin (GA) is a single-stranded protein obtained by hydrolysis of collagen, with favorable biocompatibility, biodegradability and nontoxicity, and has been utilized extensively in the food, pharmaceutical and photographic industries [13–15]. However, due to the solubility in aqueous solution and poor mechanical properties, gelatin nanofibers usually require modification by chemical cross-linking agents [16,17]. Bigi et al. [18] investigated the mechanical and swelling properties of glutaraldehyde (GTA) crosslinked gelatin films, and found that the use of GTA allowed to regulate the physical-chemical properties of gelatin films. But the residue and cytotoxicity of chemical agents have limited its application in the food field [19].

Various studies have shown that many synthetic polymers such as poly(caprolactone) (PCL), poly(glycolic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) can be used with natural polymers to produce polymer composites with improved performance [20–24]. Among these synthetic polymers, nylon 66 (polyamide 66, PA66) is a multifunctional synthetic thermoplastic polymer broadly used in textiles, parachutes, biomedical fields, and functional materials [25]. It was reported that PA66 has been successfully used to modify epoxy resins to achieve tensile toughness enhancement [26], however there has been limited work related to the use of PA66 for the modification of natural polymers, especially gelatin. Owing to its anti-abrasion resistance, high mechanical strength, light weight, relatively low cost and, very importantly, biological safety [27–31], PA66 can be used as a potential modification material for gelatin.

In this work, SBS was used to rapidly fabricate GA/PA66 composite nanofiber films to address the need for food packaging materials to be prepared on a large scale. The feasibility of PA66 as the modifier to enhance comprehensive performance of gelatin in mechanical properties and the ability to resist dissolution was evaluated. The morphology, diameter distribution, molecular interaction, crystal structures, thermal stability, mechanical strength, water contact angle (WCA) and water vapor permeability (WVP) of the GA, GA/PA66 and PA66 films were characterized. In addition, the prospects of SBS for rapid preparation of food packaging are discussed.