Practice-based research networks (PBRNs) rely on a cadre of engaged members to participate in research projects. As pharmacist PBRNs increase in number, it is helpful to understand how members of other professions view their own participation in PBRNs and potential collaborative research endeavors with pharmacists. Due to their longer history of PBRN experience, physician PBRN members may have helpful advice for the establishment of pharmacy networks. The objectives of this study were to describe perceptions among a group of physician PBRN members about: Advice for developing a pharmacist PBRN, practice aspects that might benefit from collaborating with pharmacists who are part of a PBRN, and benefits and challenges of PBRN member participation. This study employed qualitative research methods. Semi-structured interviews were conducted with physician members of the Oklahoma Physicians Resource/Research Network, a primary care PBRN. Advice for establishing a pharmacist PBRN included identifying a champion, recruiting a core group, and conducting a needs assessment. Collaborative areas of interest included medication use management, patient education on chronic disease states, and physician education on new therapies. Participation benefits were categorized as personal satisfaction, improvement in practice quality improvement, advancement of specialty, peer interaction and learning, and real-time information and support. These findings offer insight into strategies for developing and sustaining pharmacist PBRNs and may inform pharmacist PBRN initiatives related to development, member recruitment and retention, and interprofessional project planning with physician PBRNs. The translation of research findings into practice relies heavily on studies that address problems that are relevant to and intended to improve practice . PracticThe Agency for Healthcare Research and Quality (AHRQ) defines a primary care PBRN as “a group of ambulatory practices devoted principally to the primary care of patients, and affiliated in their mission to investigate questions related to community-based practice and to improve the quality of primary care” . A totalJournal of the American Pharmacists Association (JAPhA) published a themed issue on recommended strategies and practitioner–academic collaborations for forming PBRNs  and we co-manage patients.” Participant #13 remarked, “A lot goes on with my patients in the community that I’m not always really aware of, and so I think the more closely we can work together, the better we can both serve our patients.” This sentiment was also expressed by Participant #9: “I believe that my knowledge goes up to a certain point and then after that, I have to depend on those experts. And when I’m dealing with medications, that has to be a pharmacist.”Several themes emerged related to how the participants described benefits and challenges of their PBRN participation. Benefits were categorized as personal satisfaction, improvement in practice quality improvement, advancement of specialty (family medicine), peer interaction and learning, and real-time information and support. Challenges described by participants were categorized as time investment, project funding, staying connected with the PBRN, and organizational support. A list of exemplar participant quotes related to each theme is provided in With regard to real-time information and support, these benefits were primarily accomplished through the Network’s email listserv, which permitted members to ask fellow Network colleagues patient care questions and receive quick responses. Other uses of the listserv included medical literature updates, Network study results, descriptions of best practices, and weekly influenza updates obtained through the State Health Department during flu season. Members also valued testing state-of-the-art health information technology in various studies.Interacting with and learning from peers, especially from more experienced peers, was viewed as beneficial. As one participant stated, “What you get is not the ‘book’ knowledge, but the knowledge of experience.” Participants in rural and academic settings noted that interacting with their peers helped alleviate feeling isolated from their colleagues. The Network’s annual convocation was mentioned as a valuable forum for socializing, professional interactions, and learning.Practice quality improvement was observed as an advantage of PBRN participation. By being involved in research, participants were able to adapt their practices, receive feedback to improve, and see meaningful results for their patients. PBRN participation also kept them up to date with relevant topics.Beyond improvements in their own practices, participants viewed advancing their specialty of family medicine as beneficial. Participants remarked how family medicine struggles for recognition and parity in billing with other medical specialties. Having multiple family medicine practices in the Network involved in research was seen as lending credence to the specialty, strengthening professional identity, and reaffirming that there is power in numbers.Participants commented that they experienced personal satisfaction through PBRN participation. This satisfaction manifested as feeling excited about research involvement, energized by learning, and assured as a health care provider through the dissemination of study results and receiving feedback from peers on patient care questions.PBRN participation challenges described by the physicians were categorized as time investment, project funding, staying connected, and organizational support. Time investment challenges included wishing they had time to participate in more projects and finding time to read listserv emails. Examples of project funding challenges were the need for improved contracted health services such as preventative care, recognition from funding sources that would lead to more project funding, and reimbursement for project involvement. Some physicians experienced challenges staying connected with the OKPRN due to rural isolation or distance from the Network’s administration in Oklahoma City. Other challenges experienced by these physicians included gaining approval from their employer groups to participate in Network projects and Institutional Review Board approval issues stemming from their practice settings’ organizational structures.Perspectives from 15 physician members of a primary care PBRN in Oklahoma were described. Topics included advice for developing a pharmacist PBRN, practice aspects that might benefit from collaborating with pharmacists who are part of a PBRN, and benefits and challenges of PBRN participation. When sharing lessons learned from its initial years as a pharmacist PBRN, researchers and network leadership from Rx-SafeNet noted the benefits of conducting “pre-launch” surveys to assess perspectives from potential PBRN members and developing project topics that were relevant to members . This enThe identification of a pharmacist champion and a core group of pharmacists was described as an essential activity to developing a PBRN. These pieces of advice parallel the use of luminaries in Community Pharmacy Enhanced Services Network (CPESN®) USA, a clinically integrated network composed of approximately 2250 community pharmacies in 46 local CPESNs across the U.S. ,49. The Identifying mutually relevant problems that physicians and pharmacists face is an important step to find collaborative solutions that may be examined through practice-based research. Researchers at the University of Wisconsin–Madison used a multi-step interview process to bring together dyads of physicians and pharmacists to describe mutually agreed upon problems and to propose collaborative solutions . SimilarThe physicians in the present study discussed their experiences and what PBRN participation means to them. Similarly to previous studies of pharmacist PBRN members ,23,24,25One of the PBRN participation challenges mentioned in the present study was lack of contracted preventative health services. Community pharmacy services aimed at medication optimization and lowering total healthcare costs rely on the notion of preventing medication-related problems that can lead to drug-related morbidity and mortality. For example, the costs of monitoring medication adherence and clinical parameters such as blood pressure pale in comparison to hospital admission costs and other costs associated with cardiovascular events. For sake of longevity and survival, developing PBRNs should take sustainable business models into consideration and explore stakeholder relationships that provide compensation to pharmacists for providing patient care services. The limitations of this study should be considered when interpreting the findings. The participant sample was small. Female and ethnic minority physicians were underrepresented. The perspectives of the physicians who took part in the study may have reflected PBRN members with higher degrees of involvement than their fellow Network colleagues. However, the objective of this research was to understand these perspectives to inform recruitment and retention practices by existing and developing pharmacist PBRNs. Therefore, a higher degree of engagement among study participants was desirable. The participants were from a single PBRN, and almost three-quarter were from the same region of the state. Individuals from other networks or from another part of Oklahoma may not share the same perspectives, thus potentially limiting the geographical representativeness of the study findings. More extensive studies with participants from other PBRNs may reveal additional findings. The number of interviews was determined by resources rather than thematic saturation. Probing questions pertaining to collaborative topics were used; however, the majority of participants (67%) mentioned at least two of the predetermined topics without probing. Lastly, almost one-third of the interviews were conducted face-to-face, while the remaining ones were conducted over the telephone. Despite potential differences in the dynamics between these two types of interview formats, there were no discernible differences in responses.Physician members of a primary care PBRN provided insights into practice areas that might benefit from collaborating with pharmacists who are part of a PBRN, such as optimizing medication use (improving patient adherence and reducing medication errors) and patient education on chronic disease states. These findings offer insight into strategies for developing and sustaining pharmacist PBRNs and may inform pharmacist PBRN initiatives related to development, member recruitment and retention, and project planning. Various opportunities exist to conduct interprofessional research between pharmacist and physician PBRNs.


The relationship between child abuse and the use or abuse of alcohol has two aspects. First, some findings have indicated that parental alcohol abuse may be associated with the physical or sexual abuse of children. Research findings in this area remain inconsistent, however. Second, the experience of being abused as a child may increase a person’s risk for alcohol-related problems as an adult. This relationship has best been demonstrated in women who had been victims of childhood abuse. Several factors most likely contribute to or influence this relationship, including coping skills; antisocial behavior; and psychological problems, such as posttraumatic stress disorder. According to research estimates, each year more than 1 million children in the United States experience some form of abuse or neglect . Child aChild abuse manifests in various forms, including physical abuse, sexual abuse, neglect, and emotional or psychological abuse . PhysicaThe first part of this article reviews studies assessing the alcohol-related and non-alcohol-related factors that might contribute to parental child abuse, although these studies have produced inconsistent findings.The second part of this article includes more conclusive research findings concerning the relationship between childhood victimization, particularly childhood abuse and neglect among women, and subsequent adult alcohol abuse. Within this discussion, the article explores how future research may identify further characteristics that could increase a person’s risk for developing alcohol abuse as a consequence of childhood victimization.Researchers have suggested that numerous factors play a role in parental child abuse. Some factors directly relate to parental alcohol abuse, whereas other factors do not—or only do indirectly.Although many people might intuitively assume that parental alcohol use and abuse contributes to child abuse, research in this area frequently has produced inconsistent results . For exaDespite improvements in methodology, more recent studies also have found inconsistent results regarding the association between parental alcohol use and child abuse. For example, a study among college students evaluated the participants’ recollection of childhood physical, sexual, or emotional abuse and of parental alcoholism, but found no significant relationship between parental alcohol use and the various types of child abuse . ConversOther studies have determined the child abuse potential  of parents with and without histories of alcohol and other drug (AOD) abuse. On the assumption that a relationship does exist between parental alcohol problems and child abuse, researchers have begun to speculate about some of the possible mechanisms linking these problems. For example, The cognitive disorganization hypothesis posits that alcohol abuse increases the likelihood of violence, because it interferes with communication among family members and results in misinterpretation of social cues, overestimation of perceived threats, and underestimation of the consequences of violence.deviance disavowal hypothesis suggests that the perpetrator attributes the violence to his or her alcohol abuse and thus avoids or minimizes personal responsibility for the violent behavior.The disinhibition hypothesis proposes that alcohol’s pharmacological actions on the brain interfere with the actions of those brain centers that control  socially unacceptable behaviors.The The relationship between parental alcohol abuse and childhood sexual abuse (CSA) may be even more complex, because the perpetrator of the abuse may be the alcohol-abusing parent or another person.The mechanisms underlying this association between parental alcohol abuse and CSA remain unclear. Possibly, parental alcohol abuse increases children’s vulnerability to CSA by interfering with the parents’ ability to provide a supportive, nurturing, and protective environment . For exaSeveral studies have identified low SES as a factor contributing to child maltreatment . In addiResearch shows that a stressful relationship between parents can markedly increase the risk of child abuse see . For exaSome studies have suggested that a parent who experienced abuse as a child is more likely to be abusive toward his or her own children, although this connection has not been thoroughly confirmed by research. For example, based on a literature review, Numerous investigators have analyzed the relationship between childhood physical and sexual abuse and the development of adult alcohol problems. Most of these studies have been conducted retrospectively—that is, adolescent or adult study participants with or without alcohol problems were asked about their childhood experiences of abuse e.g., . Fewer sFew studies have investigated the relationship between childhood victimization and later alcohol use in men. In a prospective study, Most studies on the correlation between childhood victimization and adult alcohol abuse have been conducted in women. These analyses have used a variety of samples, including women in the general population, women with court-documented histories of childhood abuse or neglect, and women undergoing alcoholism treatment. With a few exceptions , most ofAlcohol consumption in the 30 days before the survey interviewIntoxication in the year before the survey interviewOne or more alcohol-related problems  in the year before the interviewOne or more symptoms of alcohol dependence  in the year before the interview.In another community-based study, As mentioned earlier, Finally, as mentioned earlier, abused and neglected males in the same study had no increased risk of adult alcohol problems compared with control males. The researchers suggest that the gender difference may result in part from differences in how men and women respond to childhood victimization. For example, one common theory is that men may be more likely to express themselves through externalizing behavior . Conversely, women may be more prone to internalizing pain and suffering, which then may lead to self-destructive behaviors, including alcohol abuse . AnotherOther researchers investigated the prevalence of CSA and other forms of childhood victimization among women undergoing alcoholism treatment and various control groups . In thatIn summary, various studies on the relationship between childhood victimization and adult alcohol-use behaviors have yielded inconsistent results, although several studies have indicated that particularly among women, childhood abuse and neglect may increase the risk for adult alcohol problems. Additional research is needed to clarify this relationship and identify factors that may influence it. Some of those factors are described in the following section.Researchers have proposed several hypotheses as to why victims of child abuse and neglect may be at increased risk for alcohol abuse during adulthood. Thus, alcohol may serve as the following see :A mechanism to cope with or escape from the trauma of childhood victimization and the related depressionA way to reduce feelings of isolation and lonelinessSelf-medication in an attempt to gain control over the experienceA way to improve self-esteemA form of self-destructive behavior.Accordingly, factors such as poor coping skills, antisocial behavior, and abuse-related posttraumatic stress disorder (PTSD) may help mediate the relationship between childhood victimization and adult alcohol problems.Researchers have suggested that for some victims of childhood abuse, alcohol may serve as a coping mechanism to deal with the trauma associated with the abuse and its consequences . For exaSeveral studies among children and adolescents who had experienced child abuse found that externalizing and antisocial behaviors  can be a consequence of childhood victimization see , 1997. IThe relationship between childhood victimization, antisocial behavior, and adult alcohol problems may apply particularly to victims of child abuse with family histories of alcoholism. Research shows that children of alcoholic parents are at increased risk for alcohol problems themselves  and thatResearchers have identified several types of alcoholism, one of which is characterized by high levels of antisocial behavior that frequently begins manifesting during adolescence. Children whose parents have this type of alcoholism may be particularly likely to be abused during childhood. In addition, those children are at increased risk for antisocial behavior and subsequent alcohol problems themselves, both because of a genetic predisposition and because of the experience of child abuse. Therefore, future studies of the link between child abuse and later alcohol abuse need to address the potentially confounding effects of a genetic predisposition for alcohol problems .PTSD is caused by a person’s experience of an extremely stressful situation, such as threatened or actual violence toward the person or toward someone close to that person. Symptoms of PTSD include persistent recollections  of the trauma, avoidance of any stimuli  associated with the trauma, and persistent symptoms of increased arousal . PTSD is a relatively common consequence of physical or sexual child abuse , and resIn another study, Researchers have studied alcohol abuse as both a contributor to and a consequence of child abuse. To date, studies have not determined conclusively the role of parental alcohol abuse in the perpetration of physical or sexual child abuse or neglect. However, several studies have indicated that parental alcohol abuse may increase a child’s risk of experiencing physical or sexual abuse, either by a family member or by another person. Furthermore, researchers have proposed several hypotheses regarding the mechanisms through which parental alcohol abuse might contribute to the abuse or neglect of children.The relationship between childhood victimization and adult alcohol abuse appears somewhat more solid, particularly for women who were victims of child abuse and neglect. Thus, studies using various types of samples found that women who had experienced childhood maltreatment were more likely to have alcohol problems as adults than other women and that women undergoing alcoholism treatment were more likely to have been victims of childhood victimization than other women. Too few studies have investigated the relationship between childhood victimization and adult alcohol use among men to permit firm conclusions, but the evidence so far indicates that child abuse and neglect is not an independent risk factor for subsequent alcohol problems in men. Further research is greatly needed in this area. Additional research also is needed on the factors that mediate or moderate the link between childhood abuse and adult alcohol-use patterns. Researchers have suggested several such factors, such as inadequate coping skills, antisocial behavior, and PTSD, but the exact roles of these factors must be elucidated further.Once the mechanisms underlying the relationship between child abuse and adult alcohol abuse are better understood, clinicians, social workers, and other interested groups can use that knowledge to intervene with the victims of child abuse and help prevent subsequent alcohol problems in those victims. For example, such efforts could be targeted at abused and neglected females (both adolescents and older women) to reduce their risk of adult alcohol problems. Because alcohol use as a coping mechanism has been identified as a mediator between childhood abuse and neglect and subsequent alcohol problems, such interventions could focus on helping those women develop more positive coping mechanisms.


While young people in sub-Saharan Africa (SSA) are at greatest risk of HIV acquisition, uptake of HIV prevention interventions among them has been limited. Interventions delivered through social connections have changed behaviour in many settings, but not to date in SSA. There is little systematic evidence on whom young SSA adults turn to for advice. We therefore conducted an exploratory cross-sectional study from whom young rural South Africans received support and sexual behaviour-specific advice.We asked 119 18–34  year olds in rural KwaZulu-Natal about the important people in their lives who provided emotional, informational, financial, physical, social or other support. We also asked whether they had discussed sex or HIV prevention with each contact named. We used descriptive statistics and logistic regression to analyse support and advice provision patterns.Respondents named 394 important contacts, each providing a mean of 1.7 types of support. Most contacts were relatives, same-gender friends or romantic partners. Relatives provided most informational, financial and physical support; friends and partners more social support and sexual advice. Respondents reported discussing sexual matters with 60% of contacts. Sources of support changed with age, from friends and parents, towards siblings and partners.Sexual health interventions for young adults in rural South Africa may be able to harness friend and same-generation kin social ties through which sex is already discussed, and parental ties through which other forms of support are transmitted. The gender-segregated nature of social connections may require separate interventions for men and women. The relative importance of family and peers to young African adults for discussion of sexual behaviour is unclear.Relatives provide the majority of financial, physical and general information support to young adults in rural South Africa.Most young adults discuss sexual matters with others, with friends and same-generation relatives providing the majority of sexual discussion and advice.Sibling, friend and sexual partner relationships represent pre-existing sexual health discussion channels that might be leveraged to provide novel information and skills.It is likely to be harder to adapt young adults’ relationships with parents to include key sexual health messages.HIV and other sexually transmitted infections (STIs) remain a significant concern in sub-Saharan Africa (SSA). This is particularly true for young people, who are at highest risk of HIV acquisition while aged under 30.One way of improving intervention engagement and uptake is delivery through peers or influential others.Stable social ties are also more likely to reflect relationships that form part of the referent group for perceived social norms—both descriptive  and injunctive Peer-led interventions have been used extensively for sexual health,A key factor in developing peer-led interventions is therefore selecting the right individuals to diffuse new ideas or behaviours. Within SSA, constraining sexual norms, with a focus on virginity and associated respectability,It is not clear who influences the sexual behaviour of young people in SSA, particularly for young adults who have left the school environment. There are no quantitative data on who young Africans talk to about important matters, including advice relating to sexual behaviour and HIV-related activities. We therefore interviewed a wide range of young people aged 18–34 in a rural and small-town South African setting at the epicentre of the HIV epidemic, in order to quantify both existing sources of sexual behaviour advice and other sources of social support that might be potential sources of such advice.2 area of uMkhanyakude district, KwaZulu-Natal.We conducted our study in November 2015 in the Somkhele demographic surveillance area (DSA) of the Africa Health Research Institute (AHRI), an ~438 kmWe interviewed 119 adults split between one of the most densely populated periurban areas and one of the least densely populated rural areas. We further stratified our sample by respondent gender and age (18–24 and 25–34). To recruit participants, we drew up maps of each area based on a census conducted earlier in 2015 and progressed door-to-door through each area between 09.00 and 18.00 on Tuesdays to Saturdays; we intentionally included a weekend day to capture some of those who work during the week. Any age-eligible individuals present and living in each household were invited to participate until each age-gender-area stratum was roughly filled. We did not go back to households whose age-eligible members were not present. Our sample size was based on the number of respondents required to provide 80% power at http://opendatakit.org). All interviews were conducted in isiZulu. Questions were developed in English, translated by experienced local translators and discussed within the study team, including bilingual members.Each interview used a mixture of computer-assisted personal interview (CAPI), led by the interviewer on a tablet computer, and computer-assisted self interview (CASI), in which the respondent entered their own responses on the tablet. The questionnaire was programmed and delivered using OpenDataKit  or considered their friends, neighbours or kin (‘interactions’), because the latter are open to wide subjective interpretation. We used six name generators covering different types were preferable to a single, ‘affective’ one  since we were interested in a range of types social support, which these name generators explicitly capture. Our five specific name generators were chosen to map to support domains in the Arizona Social Support Interview Schedule,Name interpreter questions generate information about the relationships between respondents (‘egos’) and their contacts . We asked about the nature of the respondent’s relationship with each named contact, including whether they had discussed sex or prevention of HIV and other STIs . Sexual contact name generators and interpreters and social contact interpreters relating to sexual behaviour  were asked using CASI.Public community information sessions were conducted before study commencement in both settings, to ensure the community was aware of the nature and research goals of the study. The research conformed to the principles embodied in the Declaration of Helsinki.In this analysis, we included only alters named in the social contact section, although there was overlap between alters from the sexual and social name generators. We grouped relatives into three generational categories: older, that is, parents, aunts/uncles and grandparents; same-generation, that is, siblings and cousins and younger, that is, children, nephews/nieces. We also grouped non-relatives into two categories: romantic partners and non-romantic non-relative contacts based on whether the respondent reported having ever had sex with each contact. We placed husbands/wives in the romantic partner category.We first described the permutations and combinations of support types provided by contacts visually and using pairwise Pearson correlation coefficients. We stratified descriptive statistics of contacts by the age and gender of the respondent , looking at how the relationship and gender composition of respondents varied across these four respondent categories. We then described who provided each type of social support by relationship category, before running hierarchical logistic regression models (contacts nested within respondents) to determine how support provision varied by respondent and contact characteristics. We conducted similar analyses for exchange of advice relating to sexual behaviour. We stratified all regression models by respondent gender under the hypothesis that the social dynamics of each gender were different. Analyses were conducted in Stata release 14 and figures built in R V.3.4We interviewed 119 respondents ; no non-The majority of those providing support to these young people were relatives, approximately evenly split between same-generation and older generations, with substantial minorities of non-relatives (largely friends) and romantic partners . HoweverSources of support provision varied greatly by support type . Non-rel2=5.4, p=0.02) and informational support  compared with named fathers. The proportion of named parents reported to provide physical, financial and socialisation support were non-significantly different . Several of these results were confirmed in multivariable regression models , to siblings and romantic partners. Fourth, support is primarily provided by same-gender contacts, with the notable exceptions of romantic partners and mothers (for men).The high level of support from relatives was notable across a wide range of support types. Parents and grandparents provided more informational and financial support than any other group. This pattern of support arises in a social context of generalised poverty relative to the South African average, and extremely high youth unemployment.The importance of friends and same-generation relatives for socialisation support and sexual advice is not surprising. There has been extensive research into the roles of peers, parents and media in influencing adolescent sexual behaviour in higher-income settings,The importance of gendered norms of behaviour is very clear in our data. Overall, the degree of gender homophily  is high and rises with age. Gender homophily has been seen in social networksOur findings have several implications for the design of interventions to reduce HIV and other STI risk. First, our young adults discussed sexual matters with a majority of their close social contacts, particularly peers. These relationships with siblings, friends and sexual partners represent existing channels that can be leveraged to increase knowledge, motivation and safer sex behaviour. Given the high level of gender homophily seen in these peer relationships , it is likely that interventions will need to ensure wide coverage of men and women separately, particularly for participants over age 25.Second, although young adults do not much discuss sexual matters with parents in this setting, they do continue to receive other forms of parental support, including general informational support, well into adulthood. There may therefore still be an opportunity to turn these conversations towards sexual health and protection from HIV; respondents reported having discussed HIV prevention with 35 of 100 parents named as social contacts. Past parent–adolescent communication research in SSA has shown that most communication is limited and fear based,Third, a minority of respondents (8%) who have had sex do not report having ever talked about sex or HIV prevention with any of their key social contacts. Such individuals may be at particular risk of poor sexual health outcomes and would be important to engage through any peer-based intervention strategy. It is also important to note that the substantial intraclass correlation coefficients seen in the sexual advice analyses implies that there was substantial heterogeneity in how respondents discussed sexual matters, and thus multiple approaches may be needed.Given the strong patterns of how social support varied by respondent age and gender, and social contact gender and kinship, our work presents several testable hypotheses for future larger studies.Our study should nevertheless be considered in the light of some potential limitations. First, we had limited power to see significant associations in the data for interactions and stratified analyses. While we saw substantial point estimates for interaction terms in Second, all of our data is self-reported and in this study we cannot validate respondent responses against those given by social contacts. While the topic of friendship is not typically considered a sensitive one, there may be social relationships that respondents prefer not to discuss. However, unless this social desirability bias is differential by respondent age or gender, it should not affect the key results we present here. Nevertheless, using sociocentric data methods  would allow us to validate reported relationships; this would require additional information not collected in this study, but which might be included in future work.Third, our data are cross-sectional, which does not allow us to determine whether the named contacts actually influenced the attitudes or behaviours of respondents. Future longitudinal data would allow us to determine which types of social support provision (if any) are associated with changes in attitudes or behaviours, something that is vital if we aim to select specific social contacts to act as assistants in the delivery of HIV-related interventions.Finally, the findings in this study are likely to be specific to rural and small-town African settings, possibly only within South Africa or even KwaZulu-Natal. Social dynamics in cities, where a greater range of social contacts are available, may be very different from those in more sparsely populated areas. Findings in this study could thus usefully be compared with future work in other South African and African settings.In this study, we showed that young adults who are members of a cohort at substantial risk of acquiring HIV and other STIs in rural and periurban South Africa receive social support from a range of different sources, and that these sources are strongly affected by gender and to a lesser extent by age. These results suggest that there may be a clear opportunity to harness peer and kin social networks to deliver effective HIV prevention interventions. However, any effort to influence the attitudes, beliefs and behaviours of these young adults via their friends and family will need to be tailored by age and gender.


Chronic pain afflicts as much as 50% of the population at any given time but our methods to address pain remain limited, ineffective and addictive. In order to develop new therapies an understanding of the mechanisms of painful sensitization is essential. We discuss here recent progress in the understanding of mechanisms underlying pain, and how these mechanisms are being targeted to produce modern, specific therapies for pain. Finally, we make recommendations for the next generation of targeted, effective, and safe pain therapies. Pain represents a major challenge to modern medicine. Chronic pain is the most common neurological disorder and migraine, a subtype of pain, is the most common reason for presentation to a neurologist. Chronic pain is exceptionally disabling, and assessments of the global burden of disease consistently rank headache and low back pain as the diseases causing the greatest global disability burden . ChronicPain is currently stratified into chronic, subacute, and acute pain. Chronic pain is defined as persistent or recurrent pain that lasts longer than the typical healing process often arbitrarily considered 3 months; acute pain being that lasting under 6 weeks and subacute pain lasting between 6 and 12 weeks . Since aInflammatory pain disorders include pain caused by inflammation generally elicited by some kind of noxious insult or degeneration for example the disorders of rheumatoid arthritis, osteoarthritis and after tissue trauma where inflammatory mediators and immune cells are recruited and secrete inflammatory mediators directly causing peripheral sensitization and later central sensitization. Inflammatory disorders are more commonly associated with hyperalgesia rather than allodynia. These conditions remain highly prevalent and are becoming more so with an aging population given that many are age-related conditions. Inflammatory pain is likely a protective phenomenon; when injured it is necessary to prevent use of the affected area to promote healing.Neuropathic pain disorders are among the most treatment resilient pain conditions. Unlike inflammatory pain, neuropathic pain appears entirely maladaptive. Neuropathic pain by definition involves lesion or inflammation of the nervous system and includes diseases such as trigeminal neuralgias, peripheral neuropathies, and post-herpetic neuralgia. The uniting factor is the etiology of lesion to peripheral or central nervous system , althougDysfunctional pain disorders include bladder pain syndrome  , irritabPeripheral sensitization can be a feature of any type of pain. It is defined as any increase in the responsiveness of the nociceptive circuit at the level of the periphery and a lowering of the threshold at which pain is perceived. Primarily, there is the peripheral release of the ‘inflammatory soup’  consistiThe innate immune system has a major role in driving nociceptive hypersensitivity. Macrophages, a major component of innate immunity, plays dual roles during injury: they act to promote inflammation, and drive the immune response to non-host factors (in the M1 macrophage state) triggered by interferons, bacterial infection markers and other immune mediators; and conversely (in the M2 state) act in an opposing manner and behave in an anti-inflammatory, healing and repair-focused state, triggered by mediators like Il-4 . When inThis role of the immune system in pain sensitization is not limited to the innate immune system, with the adaptive immune system also playing an important role in modulating nociceptive hypersensitivity. T cells including Th1 and proinflammatory Th17 subsets play a role in neuropathic pain by acting as a source of IFN-γ, chemokines, and IL-17A. IL-17A acts at nerve terminals to sensitize nociceptors by decreasing the rheobase  . The adaThe interaction between nociceptors and immune cells is not limited to the site of injury as immune cells also interact with nociceptor cell bodies within the DRGs to produce pain, alter protein synthesis and induce sensitization  Many disThe inflammatory mediators have a number of targets of action. Some of these molecules directly activate or modulate nociceptors, for example protons that directly enter terminals. Other molecules such as prostaglandins, bradykinin and ATP have their own receptors coupled to signaling cascades that enhance neuronal activity. Activation of these signaling cascades can cause modification of existing channels, an upregulation of trafficking of receptors or the downstream regulation of transcription.Growth factors such as NGF, are important regulators of neuronal survival during development . HoweverCytokines are small secreted proteins that include chemokines, interleukins, TNFα, colony stimulating factors, and interferons among others. Cytokines have a major established role in pain sensitization.Pro-inflammatory cytokines, are a major class of secreted cytokines that include TNFα, IL-1, IL-17, IL-2, IL-4, and IFN also play a major role in nociceptive hypersensitivity. These molecules can have a major role in promoting hypersensitivity. This role is partly through activation of other local cells. For instance, TNF-alpha activity can induce IL-1β and NGF expression to increase pain sensitivity . PrimaryChemotactic cytokines, known as chemokines, have a particular established role in pain. By definition, in the immune system, these molecules have a chemotactic effect and a major part of their role in pain sensitization is recruitment of immune cells. However, many chemokines have receptors on sensory neurons that are directly activated GPCRs, able to modulate receptors and coupled to their own signaling cascades, for example CCL3 can sensitize TRPV1 currents , and CCLex vivo. Furthermore when IBS patients are treated with Ebastine, an antagonist for the H1 receptor, visceral neurons become significantly less sensitive, and in patients who had visceral hypersensitivity, their sensitivity reduced  show rapid adaptation in response to tonic mechanical stimuli and are not able to properly encode repetitive stimuli. Moreover, mechanical sensitization does not occur, hypersensitivity and paw edema were reduced after paw incisions (Neuropeptides such as bradykinin and tachykinin are important nociceptor sensitizing agents released during tissue damage . For insncisions . Whilst ncisions . Part ofAnother major class of inflammatory mediators are arachidonic acid and its lipid metabolites. A key group of lipid mediators are eicosanoids including the prostacyclins and the prostaglandins (PGE2), which induce nociceptor hypersensitivity. During inflammation the enzyme cyclo-oxygenase (COX), converts arachidonic acid to eicosanoids including PGE2 which increase nociceptive sensitivity, PGE2 sensitizes nociceptors partly through sensitizing TRPV1 responses through PKC and PKA activity . There aNon-host factors from bacteria, venoms, virus and parasites mediate sensitizing responses in nociceptive sensory neurons and may cause pain . This paAfferent associated glia play an important role in sensitizing responses. In part peripheral glia may act as damage sensors. CCL2 for instance induces the migration of macrophages, which signal to Schwann cells to maintain the infiltration of macrophages and ongoing allodynia .Recent evidence suggests that skin-resident peripheral glia, and in particular activation of specialized Schwann cells that act as mechanotransducers, are both necessary and sufficient for mechanical pain sensation , howeverAs alluded to these mechanisms function at a transcriptional and post-translational level to initiate pro-sensitization cascades that drive peripheral sensitization. Activation of p38 mitogen activated protein kinase by signaling cascades for instance is sufficient to further stimulate the transcriptional upregulation of TNF-α and IL-1β which then feedback to amplify the inflammatory response and maintain nociceptive sensitization.Central sensitization refers to the increase in nociceptive sensitivity driven following injury at a central rather than a peripheral level. This is not narrowly defined, so some of these mechanisms also function at the level of the brain rather than solely at the level of the spinal cord . MoreoveOver recent years it has become increasingly apparent that multiple cell types are involved in the transition to chronic pain following injury. Some researchers have attempted to define the causes of these sequential responses. For example, ERK activation occurs in many spinal cord cells in a particular order. Using ERK phosphorylation as a surrogate for activation, it is apparent the first cells responding to nerve injury are neuronal and then microglia follow in the early (<2 days) phase, while astrocytes are activated last . It is cAstrocyte activation has been associated with mainly the late (maintenance) phases of neuropathic pain. Ablation of astrocytes using intrathecal astrocyte targeted toxins is able to reverse established neuropathic pain (>10 days in rats), although curiously this represents only a transient effect suggesting that inhibiting astrocytic activation alone is not a viable strategy for the alleviation of neuropathic pain. Moreover, spinal nerve ligations (SNLs), a model of neuropathic pain, induce the activation of cJUN in spinal astrocytes and inhibition of cJun activity is able to therapeutically reverse established neuropathic pain . AstrocyFollowing tissue damage, inflammatory mediators are released into the spinal cord in much the same way that peripheral sensitization happens at the periphery. A key target and source of these inflammatory mediators is the microglia. In particular the spinal upregulation and activation of ionotropic, purinergic (ATP) receptors P2X7 and P2X4  triggersin situ hybridization have suggested that BDNF is not expressed in naïve spinal microglia  receptor opening. The NMDA receptor is blocked at rest by a magnesium ion in its pore  to occur wherein there is synaptic strengthening and a lower threshold is required to elicit a depolarization . Similarits pore . The coiits pore  and partits pore . Howeverits pore  but p38 its pore . Moreoveits pore  suggestiits pore  and encoDrosophila shows that this loss of inhibition is a strongly conserved mechanism essential for at least some forms of nerve injury associated hypersensitivity  2, and reversing this using Histone deacetylase (HDAC) inhibition relieves aspects of neuropathic pain (Gad2 (encoding for GAD65) transcripts are decreased in the spine although it is unclear whether this change is driven by transcriptional downregulation or a loss of neurons , following Nerve injury and CFA injection in Rats, there is a decline in hic pain . This re neurons . There i neurons  in centr neurons  however, neurons . MoreoveThe system shows additional complexity as the reduction in GABA is not limited to the spinal cord. At least in neuropathic human patients there is a loss of central GABA using quantitative magnetic resonance spectroscopy, a method by which an MRI can resolve the molecular composition by examining the amino acid concentrations of a specific space. The only study so far to utilize this technique showed that there was a significant decrease in the levels of GABA in the contralateral thalamus . This suggests multiple levels of regulation of pain transmission including multiple levels of inhibition . The utiSuperficially alleviating pain is obvious , treatinAddiction due to pain relief now represents a major crisis in medicine. Since the early 1990s, opioids have played a much more important role in treating pain in the community, with devastating results . Opioid Many current methods for relieving pain diseases in the long-term, such as low back pain, lack a solid evidence base from randomized clinical trials . In partWhilst the relief of nerve compression can promote long-term relief in certain cases of trigeminal neuralgia, where there is microvascular compression of the trigeminal nerve, in general this kind of surgical approach is unsuitable for most forms of neuropathy which lack an obvious mechanical etiology. A number of more recent approaches have been created in an attempt to address the lack of long-term therapies. The most obvious local therapies for pain that show considerable efficacy in small animal models are nociceptive ablation using high doses of specific agonists and blocking transmission, for example using local anesthetic injections. However, the use of non-specific local anesthetics is associated with considerable side-effects since they are not selective to particular voltage gated sodium channels and nociceptor ablation using capsaicin creams shows only mild efficacy in the clinic . FinallyCurrent pain relief works in a non-specific manner, In general current treatments for neuropathic pain focus on the block of signaling pathways  and the enhancement of descending control (for example opioids). For instance Gabapentinoids are largely calcium channel blockers originally developed for the treatment of epilepsy, conversely carbamazepine, an effective drug for trigeminal neuralgia blocks sodium channels. There are clear issues with this strategy. In general the nervous system uses conserved pathways for activity, whilst this means that drugs targeting other diseases, in particular epilepsy, are available, this also contributes to the broad array of side effects . Many ofChronic pain and related conditions such as addiction impose a significant affective disease on people. Existing pain treatments do not adequately address the burden of living with pain in part because they do not address the affective component. Chronic pain often co-occurs with serious psychiatric diseases such as depression and anxiety. There is evidence that chronic pain may directly contributes to these conditions and acute pain causes depressive symptoms in mice through a central mechanism . Pre-exiExisting treatments and some emerging therapies retain limitations in their ability to promote functional recovery. Firstly, the aforementioned pain comorbidities can make functional living difficult, including maintaining employment and additional costs related to healthcare are associated with residual pain. Beyond this, not effectively treating pain can be dangerous. There is evidence that patients tend to self-medicate, often with harmful consequences such as high alcohol intake or the use of drugs . WithdraAt least part of the difficulty in treating pain is the biological heterogeneity of painful disorders. Superficially similar disorders such as neuropathic pain can have varying treatment efficacies that are even dependent on location of pain. For instance, trigeminal neuralgia, a neuropathic pain subtype specifically affecting the trigeminal nerve is unique in its strong therapeutic response to carbamazepine . StratifWhilst there are many available treatments for the short-term relief of pain, it has proved difficult to relieve pain in the longer term in any mammalian system without substantial side effects. This is particularly the case for neuropathic pain. A key reason for this is that current available therapies for neuropathic pain focus on the block of peripheral or central neurotransmission rather than altering factors underlying the maintenance of pain such as glial activation, central sensitization and loss of inhibition. Furthermore, all systemically acting drugs have potential for widespread side effects given their lack of specificity for neurons in the pain pathway. Historical approaches to the problem of intractable chronic neuropathic pain have been largely surgical, and the majority of these approaches revealed a singular truth, simply lesioning parts of the nervous system does not create pain relief in the long-term and many of these procedures had considerable adverse effects . The expGene therapies have been increasingly proposed to treat intractable pain. Early methods involved the gene transfer using GAD65 using herpes simplex viral vectors to enhance inhibitory tone . More rein vitro expansion of mesenchymal stem cells appears to cause an increase in their immunogenicity and autologous mesenchymal-type stem cells including BMSCs may be subject to NK-cell mediated lysis in vivo , that causes transcriptional silencing through depositing repressive H3K9me3 (Histone 3 Lysine 9 Trimethylated) marks can be achieved. This showed some promise in an  in vivo .SCN9A) mutations, Nav1.7 has emerged as a key drug target. Since Nav1.7 initially appeared to only be required for smell and pain (Since the discovery of congenital insensitivity to pain linked to Nav1.7 (and pain , it was and pain . Nav1.7 and pain . Howeverand pain . If neurand pain . If the and pain  again taChironex fleckeri, can be inhibited by targeting mechanisms linked to its ability to cause cell death specifically by treating with a cyclodextrin that removes cholesterol from cellular membranes is able to attenuate acute pain, sensitization and necrosis in mice (Chironex fleckeri envenomation remains rare, targeting snake envenomation using similar approaches may have potential for neglected tropical diseases that are having a growing impact owing to increased costs of anti-venoms and lack of antivenom efficacy in many cases (Toxins can cause substantial pain and suffering, in the case of toxin-induced pain, directly inhibiting toxin actions using molecular antidotes should be regarded as a potential therapy for pain. For example, the severe pain induced by venom from the box jellyfish,  in mice . Whilst ny cases . Similarny cases , these cny cases . Given tny cases  and thisMycobacterium ulcerans can elicit analgesia (In addition to targeting these non-host factors, toxins and venoms seem to be an effective source of potential new analgesic compounds. Through an understanding of the components of venoms and toxins, many therapeutic compounds can be identified. For instance mycolactone from nalgesia  through nalgesia . Similarnalgesia . The delnalgesia . Currentnalgesia .Whilst a lot of progress has been made developing therapies applied early in injury, prior to injury and during injury, more limited progress has been made in finding treatments for established neuropathic pain. Given that many patients have lived with pain for years, and patients who will go on to develop chronic pain are not necessarily easy to identify, it is unclear if the models we are currently using can identify effective treatments and moreover it is unclear the extent to which these pathologies are being effectively modeled in mice. With only a select few examples, in most studies the time frame of analgesia development is still limited to 3 weeks and most therapies are not tested for long-term efficacy. Examining therapies in the context of long-term treatments and efficacy is critical to developing new therapies that work in the clinic.Chronic pain was historically seen as a symptom of a disease rather than a disease in its own right. Modern therapies for pain will need to consider pain as a disease in its own right and therefore we should take a mechanistic approach to its treatment. Pain should also be regarded as a highly heterogeneous disorder. In all probability, many pain mechanisms function together to create a complex pathological disorder. Studies must now look to address which of these mechanisms function together, and examine cross-talk between different pathways in greater depth. By understanding potential cross-talk and convergence between these mechanisms, we are likely to gain a better understanding of pain targets. Furthermore if we accept that pain is a heterogeneous condition, the stratification of patients by mechanism of action may be essential for effective treatments. Beyond pain itself we must not ignore the negative psychological and social effects of pain. We know that treating a disease alone is not necessarily enough to solve pain, we should accept that resolution of pain whilst ignoring the affective components of the disorder and the central components of the disease may be similarly ineffective.Pain therapy itself is in crisis; addiction and poorly targeted drugs plague our current strategy for alleviation of chronic pain. Therefore, disease-modifying therapies which address central and peripheral sensitization are urgently needed. Whilst developing these new therapies we must be more careful to only recommend treatments with good evidence of efficacy obtained from randomized clinical trials and not subject patients to un-necessary and dangerous treatments. Finally, modern pain therapies should use targeting strategies that specifically target nociception and pain and move away from promiscuous drugs that have off-target central modulatory effects that underlie many of the side effects of analgesia. As we gain a deeper insight into the central mechanisms of pain disorders, we should be better able to treat pain diseases.JM wrote the manuscript with assistance from TC, MW, and JNM contributed to editing and figure preparation. GN edited the manuscript and supervised the work.JM and GN declare patent interests in pain therapies. The remaining 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.


It is important to find new treatments for addiction due to high relapse rates despite current interventions and due to expansion of the field with non-substance related addictive behaviors. Neuromodulation may provide a new type of treatment for addiction since it can directly target abnormalities in neurocircuits. We review literature on five neuromodulation techniques investigated for efficacy in substance related and behavioral addictions: transcranial direct current stimulation (tDCS), (repetitive) transcranial magnetic stimulation (rTMS), EEG, fMRI neurofeedback and deep brain stimulation (DBS) and additionally report on effects of these interventions on addiction-related cognitive processes. While rTMS and tDCS, mostly applied at the dorsolateral prefrontal cortex, show reductions in immediate craving for various addictive substances, placebo-responses are high and long-term outcomes are understudied. The lack in well-designed EEG-neurofeedback studies despite decades of investigation impedes conclusions about its efficacy. Studies investigating fMRI neurofeedback are new and show initial promising effects on craving, but future trials are needed to investigate long-term and behavioral effects. Case studies report prolonged abstinence of opioids or alcohol with ventral striatal DBS but difficulties with patient inclusion may hinder larger, controlled trials. DBS in neuropsychiatric patients modulates brain circuits involved in reward processing, extinction and negative-reinforcement that are also relevant for addiction. To establish the potential of neuromodulation for addiction, more randomized controlled trials are needed that also investigate treatment duration required for long-term abstinence and potential synergy with other addiction interventions. Finally, future advancement may be expected from tailoring neuromodulation techniques to specific patient (neurocognitive) profiles. Addiction is a burdensome public health concern that not only affects the addicted individual but also greatly impacts his or her family members and surroundings. Though several treatment options are available, many patients show a chronic course of addiction with abstinence rates between 40% and 60% 1-year post treatment  and transcranial direct current stimulation (tDCS) have been used most frequently for treatment of addiction. Other neuromodulatory options for addiction are deep brain stimulation (DBS), and neurofeedback which can be applied with Electroencephalography (EEG neurofeedback) or functional magnetic resonance imaging (fMRI neurofeedback). These techniques have been investigated as stand-alone or add on treatment and while some have been around for decades (EEG neurofeedback), others have just emerged as promising intervention for addiction (fMRI neurofeedback). In this review we will evaluate, compare and discuss the experimental application of these neuromodulation techniques for treatment of addiction.A complicating factor in the application of neuromodulation for addiction is its heterogeneity, with large individual differences in underlying brain abnormalities . With this aim we searched MEDLINE databases using PubMed for the indication terms: (addiction OR substance disorder OR craving OR gambling disorder OR binge eating disorder OR bulimia OR smoking) AND . The reference lists of relevant papers were inspected for further studies that fit the inclusion criteria. The search was conducted on the literature before August 2017 without historic limitation, and only studies written in English were included. As there are large differences in number, quality and methodologies of studies between the neuromodulation techniques we used specific inclusion criteria to identify the highest quality of available evidence for each technique where we prioritize (1) sham-controlled designs (2) outcome measures focused on clinical efficacy (3) number of sessions for non-chronic neuromodulation techniques (4) and number of participants. Because of the large differences in quality and quantity of studies between the modulation techniques, we will outline which of the criteria will be applied at the beginning of each section below.Five or more stimulation sessionsInclude a sham stimulation comparator condition,Deliver stimulation with the express aim of modifying craving and/or frequency of engaging in addictive behaviors.Non-invasive brain stimulation techniques are growing in popularity as they offer a safe, economical and increasingly accessible means of modulating neural activity. The two most common and best developed methods are rTMS and tDCS. The majority of studies investigating rTMS and tDCS for addiction are single session experimental investigations that incorporate a vast array of stimulation parameters, participant characteristics, and outcome measures. The results of these studies are heterogeneous and do little to determine clinical efficacy. Of the small number of trials delivering multi-session stimulation many lack a sham condition and rely only on self-report measures, which is problematic as this does not control for placebo response or desirability reporting. Therefore, we focus exclusively on studies that meet the following criteria:>5 stimulation sessions is a substantially lesser dose than the 20–30 sessions typically considered a therapeutic course for psychiatric indications such as major depression. However, as addiction trials have delivered acute courses ranging from 5 to 13 stimulation sessions this threshold is reflective of the current state of clinical research in this area.We note that a course of tDCS involves application of a low voltage  electrical current to the scalp via surface electrodes. Current flows in one direction from a positive anode electrode to a negative cathode electrode. There are many research trials investigating tDCS, likely because of its ease of administration, low side effect profile and low cost. The strength and direction of neuromodulation effects are determined by the density, duration and direction of the current that penetrates the skull and comes into contact with underlying neurons   well controlled investigation into the impact of tDCS on selective attention and risky decision making in healthy individuals failed to replicate the prior positive findings of smaller tDCS studies  tends to have excitatory effects and is applied with intention of up regulating activity in the targeted brain region, whereas low-frequency rTMS (< 2 Hz) tends to have inhibitory effects and is applied with the intention of down regulating activity in the targeted region . Su et al.  delivereThere is a lack of controlled trials investigating rTMS for behavioral addictions. Two trials have investigated rTMS for bulimia nervosa , often conceptualized as one of the numerous presentations of food addiction, and neither found it to be effective beyond sham stimulation. Gay et al.  did not In summary, the state of evidence for rTMS for addictions is similar to that of tDCS, with a number of promising findings reported alongside numerous negative and inconstant outcomes. The diversity in outcomes likely stems from short treatment courses, variable rTMS protocols and participant characteristics, small sample sizes, and frequent use of subjective and/or short-term outcome measures Table . It is nAs a depolarizing technique that can induce focal or deep stimulation, rTMS is somewhat better placed than tDCS to target specific neural circuits and thereby specific aspects of cognitions. There are a few rTMS studies in addiction that have additionally investigated its effect on different aspects of impulsivity. Impulsivity has been associated with vulnerability for addiction  or auditory feedback. Over time the patient will then develop strategies to increase the desired brain activity or decrease the unwanted brain activity. It is therefore a less direct way of neuromodulation that involves training of the participant. Because the two types of neurofeedback that have been used to treat addiction, fMRI and EEG neurofeedback, differ much in the duration they have been used, the number of studies available, the approach , and design, we will use separate criteria for inclusion.Minimal sample size of 10 per group10 or more EEG neurofeedback sessionsInclusion of a control condition without neurofeedbackFor EEG neurofeedback many studies, case reports and case series have been published but the vast majority is of poor quality: small sample sizes, few training sessions, lack of control condition. We exclusively on studies that meet the following criteria:In contrast to EEG neurofeedback the application of fMRI neurofeedback as intervention for addiction is very new. The first studies were published in 2013 and are mostly proof of principle studies with the aim of investigating (1) whether participants can modulate the targeted brain activity (2) and whether this affects craving. No studies to date have investigated the effects of fMRI on drug use; have used sample sizes larger than 15; or used more than 3 fMRI neurofeedback visits. Moreover, only three studies used a control group  is a neuroimaging method that records electric activity of the brain through electrodes placed along the scalp. It can measure neural oscillations in specific frequency domains that are associated with functions such as attention or relaxation. With EEG-neurofeedback participants can be trained to amplify or decrease oscillations in certain frequency bands. For instance, in patients with Attention Deficit Hyperactivity Disorder EEG neurofeedback is often used to decrease theta oscillations that are related to relaxation and to amplify beta oscillations associated with concentration Butnik .With our search we found only seven studies that investigated EEG neurofeedback as treatment for substance and non-substance related addiction   investigated the effect of mixed SMR theta-alpha EEG neurofeedback on motor-impulsivity in a group with mixed-substance abuse as measured by a cognitive go/no-go task  measures increases or decreases of blood oxygenation level dependent (BOLD) response in areas of the brain indicating increased or decreased activity of that area. The main advantage of fMRI over EEG is that it can cover the whole brain  and has a much higher spatial resolution. However, preprocessing and analysis of fMRI data used to take much time and thereby made it unsuitable for direct feedback. This changed with the invention of real-time fMRI, where the data are analyzed during collection enabling direct feedback deCharms . With fMWe found 8 studies that investigated the effects of fMRI neurofeedback on craving  offers a more direct way for stimulating and modulating the brain. Powered by an implanted pulse generator, DBS provides deeper located brain areas with a continuous stimulation via surgically implanted microelectrodes. The implanted pulse generator, which is located in the pectoral area, can be manually switched on and off from outside the body and furthermore allows for modulation of stimulation frequency and intensity. Originally, DBS was introduced in the 80’s as treatment for intractable movement disorders. However, in the last 15 years it has been successfully applied in psychiatric disorders such as treatment-refractory depression and treatment-refractory obsessive-compulsive disorder (OCD). When studies reported unintended alleviation of comorbid alcohol  as these areas have been regularly used in other refractory psychiatric disorders. Luigjes et al.  studies. Currently eight studies in a total of 11 patients have specifically examined the effects of DBS on addiction related behavior  and the lateral habenula  effects on drug use, with promising results indicating the potential of these techniques for treating addiction. In this regard, the current state of research is not dissimilar to the early years of experimental rTMS for major depression, which eventually has become an effective treatment. Whether rTMS will ultimately be an effective treatment for addiction as well, awaits larger trials delivering longer treatment courses, incorporating objective and long-term outcome assessments, and systematic investigation of stimulation protocols.On the other hand, EEG neurofeedback has been investigated for decades and although one of the first studies included a sham feedback control condition , tDCS (max 10), rTMS (max 16), only in EEG neurofeedback four studies used 30 sessions or more. This might have contributed to the lack of long-term effects found by several studies: Da Silva et al.  with 5 sMoreover, the second main concern of the reviewed studies is that many of them are underpowered. Two fMRI neurofeedback studies (Canterberry et al. Neurofeedback, rTMS and tDCS have very few side effects, and are transient; therefore, they are considered safe interventions (Priori et al. One question that remains to be investigated is whether neuromodulation techniques can function as stand-alone treatments or whether they are more effective as an add-on treatment. In the majority of EEG neurofeedback studies, the treatment is provided as add-on to either pharmacological treatment or psychotherapy with the rationale that EEG neurofeedback may augment the effects of treatment as usual. Moreover, two tDCS studies used concurrent therapy (de Silva et al. A way forward in the application of neuromodulation for addiction might be to tailor these interventions to individual patients or subgroups of patients based on cognitive or neural profiles. First, this can be done by targeting specific cognitive candidates that are likely to map more closely to neural abnormalities than general addiction outcomes as craving or drug use. For instance, an overreliance on negative-reinforcement may indicate modulation of anti-reward brain network, whereas high impulsive patients may benefit more from targeting regions involved in cognitive control. Moreover, profiling based on neural functioning might be another way to investigate for which patients’ specific types of neuromodulation are most effective. Although few studies in the addiction field investigated or found effects on specific cognitive processes and none used profiling, studies in other fields show reason to be optimistic about this approach. A study that focused on rTMS for depression found that based on MRI resting state scans depressed patients can be divided in four subtypes related to specific symptom profiles that predict the response on rTMS treatment (Drysdale et al. Moreover, there are encouraging developments in other psychiatric indications for neuromodulation that show how the interaction between neurobiological science and the application of neuromodulation can mutually advance each other. For instance, a German research group found a more optimal new target for the treatment of DBS in depression, the medial forebrain bundle, based on translational neurobiological research (Bewernick et al.


Mild traumatic brain injury (mTBI) is a significant national health concern and there is growing evidence that repetitive mTBI (rmTBI) can cause long-term change in brain structure and function. The mitochondrion has been suggested to be involved in the mechanism of TBI. There are noninvasive methods of determining mitochondrial dysfunction through biomarkers and spectroscopy. Mitochondrial dysfunction has been implicated in a variety of neurological consequences secondary to rmTBI through activation of caspases and calpains. The purpose of this review is to examine the mechanism of mitochondrial dysfunction in rmTBI and its downstream effects on neuronal cell death, axonal injury and blood–brain barrier compromise. Mild traumatic brain injury (mTBI) is a significant national health concern that accounts for up to 75% of the 1.5 million TBIs sustained in the USA each year, and costs the taxpayers at least US$17 billion annually . mTBI isMost individuals exposed to mTBI recover to baseline within 3 months . HoweverAlthough the acute and long-term behavioral consequences of rmTBI have gained recent attention from researchers, the media and funding agencies, the underlying molecular mechanisms are still largely unknown. The purpose of this review is to synthesize findings relating to mitochondrial dysfunction following rmTBI and downstream effects including neuronal cell death, axonal injury and blood–brain barrier (BBB) compromise. Relevant animal models and human literature will be explored, as well as key methodology used to study aspects of rmTBI and the various mechanisms of injury .Of note, the definition of the term concussion is in discussion with regard to the clarification of the terminology. It is difficult to distinguish concussion from mTBI as there is no clear distinction in pathological findings, and inciting injuries are biomechanically similar . In addiMitochondria are membrane-bound organelles responsible for energy production via cellular respiration, which is 15-times more efficient at generating the body’s store of energy in the form of adenosine triphosphate (ATP) compared with nonmitochondrial dependent glycolysis alone . The braGrowing evidence points to mitochondrial dysfunction following rmTBI ,23–25. Tin vivo levels of biomarkers that reflect mitochondrial function. In particular, H-MRS and Phosphorus-MRS are widely employed to quantify levels of brain energetic biomarkers such as N-acetyl aspartate (NAA), ATP, lactate and nicotinamide adenine dinucleotide. The NAA molecule is synthesized from aspartate and acetyl CoA in the mitochondria [The functional state of the mitochondria following rmTBI has been indirectly assessed through the measurement of energetic biomarkers. Many of these studies used technologies such as magnetic resonance spectroscopy (MRS) that noninvasively quantify chondria , and repchondria . An incrchondria ,28–30. Nchondria .The disruption in NAA is seen in single mTBI. Govindaraju and colleagues observed decreases in NAA/Cr and NAA/Cho, markers of neuronal damage or disruption, in 14 human subjects with mTBI compared with 13 control subjects when measured within 1 month postinjury . In addiDisruption in energetic biomarkers is also evident in rmTBI. In a rodent study, decreased levels of ATP and other energetic markers was observed 2 days after rats were subjected to two mTBIs . ATP, NAIn a follow-up proton MRS study conducted in human athletes, Vagnozzi and colleagues reported findings that support the presence of mitochondrial impairment following rmTBI . AlthougA later study from the same research group involving six doubly concussed nonprofessional male athletes with interinjury interval ranging between 9 and 21 days also demonstrated that the repeat concussion increased the time of recovery of NAA/Cr ratio to baseline as well as the persistence of clinical symptoms . These rIn addition to NAA, cerebral metabolic rate of glucose (CMRgluc), calculated through spectroscopy, can also provide evidence for brain vulnerability to repeat injury. Decreased CMRgluc levels suggest metabolic dysfunction, as glucose is a substrate used by the mitochondrial and nonmitochondrial methods of ATP production. Rats subjected to a single mTBI show decreased CMRgluc in the parietal cortex and the hippocampus . CMRglucDecreased CMRgluc has also been observed in human rmTBI studies. Twelve war veterans with blast-induced rmTBI and persistent postconcussive symptoms exhibited decreased CMRgluc compared with control subjects with no history of brain injury . The decAs the evidence reviewed above suggests, there is growing evidence of mitochondrial dysfunction and brain vulnerability in rmTBI in animals and humans. Next, we review the mechanisms by which TBI may lead to mitochondrial dysfunction.in vitro study investigating the effect of rmTBI on cultured primary neurons found that glutamate release from neurons subjected to three injuries was significantly greater than those exposed to single or no injuries [+ and glutamate levels, but also decreases the clearance of glutamate from the body by downregulating glial glutamate transporters GLT-1 and GLAST [Mitochondrial dysfunction following TBI starts with an impact to the head. Acceleration–deceleration and rotational forces lead to deformation of neural tissue following TBI and trigger an outflow of potassium from the intracellular to extracellular space, with greater release following more severe injury  Figure . Next, tinjuries . As a coinjuries . TBI notnd GLAST .+ levels contribute to mitochondrial membrane depolarization [+ into the mitochondria instigates the opening of the mitochondrial PTP and disrupts the mitochondrial membrane potential via further Ca2+ influx leading to further depolarization. This ultimately leads to mitochondrial impairment by disrupting the electrochemical gradient necessary for the production of ATP. In fact, postinjury administration of mitochondrial PTP inhibitor, cyclosporin A, attenuates the disruption of the mitochondrial membrane potential and calcium homeostasis [+ homeostasis in the mitochondria and the opening of the PTP, all of which contribute to mitochondrial impairment by disrupting the mitochondrial membrane potential  . This sttoxicity . Thus, cAxonal injuries have been reported in rmTBI in animal studies  and thesEvidence suggests that even a single mTBI leads to mitochondrial damage. For example, a single instance of mTBI has been shown to disrupt energetic biomarkers in both animal models  and humain vitro study by Slemmer and Weber found greater evidence of neuronal damage in hippocampal neurons after repeated mild stretch injuries than after a single mild stretch injury [The detrimental effects seen in a single mTBI are heightened when the injury becomes repetitive. For example, rmTBI causes greater degree of neuronal damage compared with single mTBI ,69. An ih injury . In factSeveral studies have utilized cyclosporin A, a substance that inhibits the opening of mitochondrial PTP, in order to demonstrate the link between mitochondrial impairment and axonal damage. Rats given cyclosporin A 30 min before sustaining a single TBI exhibited reduced APP immunoreactivity, suggesting decreased axonal damage, when compared with the rats that were not pretreated with cyclosporin A . Buki anThus far, our review discussed the mechanisms of mitochondrial impairment post-TBI, the downstream activation of caspases and calpains as well as their harmful effects on neurons and axons. While these mechanisms have been studied more extensively in moderate-to-severe head injuries, studies show that mitochondrial impairment and axonal injury are also indicated in mTBI. The mechanism involving increased glutamate levels, opening of mitochondrial PTP and the downstream disruption of the mitochondrial transmembrane potential are suggested in mTBI. Emerging evidence suggests altered biomarker levels and poorer clinical outcomes associated with rmTBI, especially with shorter interinjury interval, compared with single mTBI. In the next section, the review investigates the effects of mitochondrial dysfunction on the BBB, an important structure that protects the brain.The mechanism of mitochondrial dysfunction may also be related to disruption of the BBB post mTBI. The BBB appropriately shields the brain from many substances in the blood; however, the integrity of the BBB may be compromised in pathological conditions, including Alzheimer’s disease, brain tumors and multiple sclerosis . BBB breSeveral studies indicate the presence of BBB compromise after a TBI. Rats exposed to a single blast-induced injury exhibited BBB breakdown in the cortex at 3 and 24 h postinjury as measured by IgG antibody staining compared with control rats . To noteAlthough human subjects have been less studied, there is some evidence of BBB breakdown in humans after mTBI. Recent findings show evidence for BBB disruption in athletes with repeated subconcussive head injuries . BBB disDespite findings demonstrating the presence of BBB compromise in mTBI, other studies show that mTBI and even rmTBI do not provide a sufficient impact to cause the breakdown of the BBB. In a study by DeFord and colleagues, mice (n = 117) that sustained head injuries using a weight-drop model (weights ranged from 50 to 150 grams dropped from 0.4-m height) were measured for IgG detection . NeitherAs discussed previously, evidence suggests that head trauma leads to the activation of caspases via cytochrome C, which can lead to apoptosis and axonal injury. The BBB is comprised of endothelial cells, basement membrane, tight junctions, astrocytic feet and pericytes, which are all involved with keeping the BBB intact  Figure . IncreasFurther, it was described earlier that rmTBI may lead to mitochondrial PT via the disruption of the mitochondrial transmembrane potential and opening of the mitochondrial PTP; interestingly, this mechanism may also be involved with BBB breakdown through the production of reactive oxygen species (ROS), a group of free radicals. Opening of the mitochondrial PTP via calcium is suggested to be accompanied by increased mitochondrial production of ROS, suggesting that PT may augment mitochondrial oxidative stress . Furtherin vitro study of cultured neurons found that those subjected to three mTBIs showed greater release of ROS compared with those exposed to single or no mTBIs [An animal study by Abdul-Muneer and colleagues further investigated the role of ROS in increasing BBB permeability in mTBI and rmTBI  Figure . Rats exno mTBIs . In anotno mTBIs . In factAn experimental animal study using cell cultures from rat and human brains supports the role ROS has in disrupting the BBB . This stWe reviewed the mechanism of mitochondrial impairment in TBI, including activation of caspases and calpains, and presented evidence of mitochondrial involvement in TBI through alterations in biomarkers. The neurological consequences of mitochondrial impairment including neuronal apoptosis, axonal injury and BBB disruption were also highlighted. Further, we provided evidence for potentially worse mitochondrial dysfunction associated with rmTBI compared with single mTBI.There remain several areas that would benefit from further research. First, there is a need to identify additional biomarkers of mitochondrial dysfunction. One promising marker that could be further explored is peripheral blood level of mitochondrial DNA post-TBI as a biomarker for cerebral mitochondrial energetics impairment . ExploraAnother area of future research is validating animal models of mTBI. There are several different methods of inducing injury in animal studies including blast and drop-weight models. While these models are valuable because they mimic different situations of TBI in the real world, it would be interesting to consider if the methods of injury have an impact on the severity of TBI. In fact, an animal study comparing lateral fluid percussion model and weight-drop with hypoxia model of comparable injury severity found discrepancies in motor recovery periods , learning and memory deficits  as well as severity of neuronal degeneration  . Thus, eMany rmTBI animal studies discussed in this review subjected the animals to two injuries. As these injuries tend to occur more frequently in certain professions, it would be important to study models that subject the animals to more than two injuries to further investigate the degree of cumulative effects of these repeated injuries. With regard to the critical interinjury interval period, it would be helpful to identify a temporal window during which subsequent injury causes a cumulative harm. Understandably, it is difficult to determine this window using animal models because the temporal window in the animal model may not translate to humans. Careful investigations with recruitment of real-life TBI patients and monitoring need to be done in order to determine this critical temporal window. By determining the critical window, one can better estimate the prognosis of negative consequences associated with repetitive TBIs with a certain interinjury interval.Evidence also suggests an association between neurodegenerative and psychiatric disorders and TBI . For exaThere has also been emerging research on the different types of therapy for patients post TBI. Examples include hyperbaric oxygen therapy, hypothermia therapy and transcranial light therapy . SpecifiMild traumatic brain injury (mTBI) is a significant national health concern and there is growing evidence that repetitive mTBI (rmTBI) can cause long-term change in brain structure and function. The purpose of this review is to synthesize the mechanism of mitochondrial dysfunction in rmTBI and its downstream effects on neuronal cell death, axonal injury and blood–brain barrier (BBB) compromise.Evidence suggests that mTBI is severe enough to induce mitochondrial dysfunction. The resulting mitochondrial dysfunction has been shown to trigger a cascade of events including ionic changes and glutamate excitoxicity that lead to activation of enzymes known as caspases and calpains. Activation of these enzymes induces many downstream effects leading to negative neurological consequences including neuronal cell death, axonal injury and BBB compromise. In addition, compared with an isolated mTBI, research suggests that repeated mTBI (rmTBI) may lead to more severe neurological consequences.The findings as a whole demonstrate that the mechanisms of mitochondrial impairment, axonal injury and BBB disruption are interconnected and very complex. In the realm of rmTBI, there may be a critical temporal window of vulnerability between injuries during which damage caused by the subsequent injury is more harmful. Further areas of research include biomarkers, different injury models, long-term effects, association with other diseases and therapy. With practical relevance of rmTBI to the general population and certain professions, this topic remains an important field of further research.


Mus musculus, Caenorhabditis elegans, and Arabidopsis thaliana. Furthermore, we consider how sex-specific changes in the meiotic chromosome axes and the epigenetic landscape may function together to regulate crossing over in each sex, indicating that the mechanisms controlling crossing over may be different in oogenesis and spermatogenesis.Meiosis is a conserved cell division process that is used by sexually reproducing organisms to generate haploid gametes. Males and females produce different end products of meiosis: eggs  and sperm . In addition, these unique end products demonstrate sex-specific differences that occur throughout meiosis to produce the final genetic material that is packaged into distinct gametes with unique extracellular morphologies and nuclear sizes. These sexually dimorphic features of meiosis include the meiotic chromosome architecture, in which both the lengths of the chromosomes and the requirement for specific meiotic axis proteins being different between the sexes. Moreover, these changes likely cause sex-specific changes in the recombination landscape with the sex that has the longer chromosomes usually obtaining more crossovers. Additionally, epigenetic regulation of meiosis may contribute to sexually dimorphic recombination landscapes. Here we explore the sexually dimorphic features of both the chromosome axis and crossing over for each stage of meiotic prophase I in  Sexually reproducing organisms pass on genetic information to the next generation through the production of haploid gametes, such as sperm and eggs. Sperm and egg development initiates with the formation of primordial germ cells during embryogenesis  homologous chromosomes must pair; (2) homologous chromosomes must repair double-strand DNA breaks (DSBs) to form crossovers, which forge a physical connection between the chromosomes; and (3) homologous chromosomes must undergo two successive segregation events. A crossover allows for accurate segregation of the homologs during meiosis I. Thus, all the preceding steps to the formation of a crossover are highly regulated to guarantee that at least one crossover is formed between each pair of homologous chromosomes. As part of the crossover regulation process, crossovers undergo a “designation” to limit the number of DSB sites licensed to mature into crossovers , or by chromatin states (Drosophila) . SYN2 and SYN4 are thought to function in mitotic cells. Knockdown of syn3 results in sex-specific differences, with female syn3 mutants displaying more severe defects than male syn3 mutants , which initiates the transition from leptotene to zygotene Fig. . The SC In some organisms, such as mice and yeast, the assembly of the SC initiates at multiple regions along the chromosomes that corresponds with sites of DSBs ; therefore, DNA methylation–mediated targeting of crossover positions may be a conserved feature of recombination control. Future studies are needed to determine how DNA methylation is acting to regulate crossover position and how DNA methylation may be influencing meiotic chromatin architecture.The regulation of these sex-biased hotspots may be controlled, at least partially, by the methylation state of the DNA. DNA is globally demethylated in the female germline, but not the male germline  an increase in crossing over .


There are two important gaps of knowledge in depression treatment, namely the lack of biomarkers predicting response to antidepressants and the limited knowledge of the molecular mechanisms underlying clinical improvement. However, individually tailored treatment strategies and individualized prescription are greatly needed given the huge socio-economic burden of depression, the latency until clinical improvement can be observed and the response variability to a particular compound. Still, individual patient-level antidepressant treatment outcomes are highly unpredictable. In contrast to other therapeutic areas and despite tremendous efforts during the past years, the genomics era so far has failed to provide biological or genetic predictors of clinical utility for routine use in depression treatment. Specifically, we suggest to (1) shift the focus from the group patterns to individual outcomes, (2) use dimensional classifications such as Research Domain Criteria, and (3) envision better planning and improved connections between pre-clinical and clinical studies within translational research units. In contrast to studies in patients, animal models enable both searches for peripheral biosignatures predicting treatment response and in depth-analyses of the neurobiological pathways shaping individual antidepressant response in the brain. While there is a considerable number of animal models available aiming at mimicking disease-like conditions such as those seen in depressive disorder, only a limited number of preclinical or truly translational investigations is dedicated to the issue of heterogeneity seen in response to antidepressant treatment. In this mini-review, we provide an overview on the current state of knowledge and propose a framework for successful translational studies into antidepressant treatment response. Major depressive disorder (MDD) is the second leading cause of disease burden worldwide, thus constituting serious socio-economic threat for modern societies , 2. CombThe choice of a particular antidepressant agent for an individual patient currently is based on treatment guidelines, experience, individual medical comorbidities, but unfortunately largely based on “trial and error” . DespiteBut how do we move from genomic variants to better treatments? Before conceptually novel and improved treatment strategies can be envisioned, we urgently need to focus on a more precise understanding of the neurobiological mechanisms underlying mental disorders and individual patient response to pharmacotherapy by appropriate translational approaches. Currently only a limited number of preclinical or truly translational investigations is dedicated to the issue of heterogeneity seen in response to antidepressant treatment.The large heterogeneity in response to antidepressant treatment  is a majAltogether, this illustrates the urgent need to develop improved translational models to better understand the neurobiological mechanisms that underlie MDD and to more specifically assess response to antidepressant treatment. We here review recent progress and highlight some of the best leads to diversify and improve discovery end points for preclinical depression research and treatment response in nonhuman organisms.Why should we use animals to model complex diseases like MDD? What could be the strengths of an animal model, and what are its limitations? From a psychiatrist's point of view, it is difficult to agree that rodent or even species such as zebrafish could be of value to investigate a complex mental disorder characterized by a set of diverse symptoms such as MDD. The same holds true for the issue of response to psychopharmacological treatment. A large heterogeneity in the symptomatology of MDD and a close association with other comorbid psychiatric disorders in a substantial proportion of MDD patients are major drawbacks and confounding factors for clinical studies . The excConstruct validity is present in MDD animal models, if depressive-like behavior and associated features can be clearly and unambiguously seen and interpreted in the model , but stratified each individual mouse based on its performance in a defined behavioral test of social interaction as outcome . StratifTo develop an approach for identifying stratification into different subpopulations out of a large number of responding animals using a low-cost animal model, we recently established an animal experimental paradigm where we analyzed the behavioral responses of a group of zebrafish subjected to stress exposure. As a vertebrate, zebrafish show high homology of the major neuromodulatory circuits involved in stress and emotional regulation. Further they exhibit behavioral phenotypes for identifying “depression-like” indices and are sensitive to different psychotropic drugs , 29. HowThus, we propose to consider individual outcomes and meaningful stratification of the experimental group instead of average group effects in animal models of depression and response prediction to improve translation between preclinical research and clinical trials. As shown in recent examples, this strategy could contribute to increased success rate when extrapolating results from the bench to the bedside and back , 30.It is still a long way to go for personalized medicine and clinically embedded prediction assays for mental illnesses. Current developments neither predict nor monitor disease state nor help with the antidepressant drug choice . Huge efFocusing on domain-based inclusion criteria for human studies bridges the gap toward animal research by overcoming the artificial, highly heterogeneous, category-based DSM-5 or ICD-10 diagnostic criteria. For a recent excellent review about the integration of RDoC criteria in animal models of psychiatric disorders see . TraditiInitiatives like RDoC might also solve or at least reduce the reproducibility problem. In a 2006 report, Hackam and colleagues showed that from 76 top-quality animal studies, only 37% could be replicated in humans, 18% were contradicted, and 34% still remained untested in humans . The medIn conclusion, we hope to have convinced the reader that animal models are pivotal in the effort to translate basic progress into better care. Because of practical and ethical limitations to dissecting neurobiological disease mechanisms in humans, continued progress will critically depend on our ability to emulate aspects of depressive symptomatology and treatment response in nonhuman organisms. Still, a significant challenge remains how to effectively align variables measured in animals with those assessed in human studies, i.e., in genetic studies or during the various phases of development of novel antidepressant compounds. This can only be achieved if translation is prospectively planned, allowing for the best possible match of recorded data across species. Translational psychiatry is a two-way bridge: research questions ideally emerge as a well-defined, clinically relevant problem that needs to be carefully translated into the best-possible animal experimental approach. On the other hand, preclinical research needs to inform clinical trials and diagnosis. Recent successful examples in depression research are encouraging and might serve as a template for future approaches into the neurobiology of this devastating and pervasive disorder.DH and MM wrote the first draft of this paper. DH, HB, KL, SR, and MM contributed to writing and discussing the paper and approved its final version.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.