There were no significant differences in acceptance rates of fair and highly unfair offers between groups, and only boys with ADHD did not significantly differ from the controls. However, the subgroup of boys with ADHD and additional high levels of aggressive CD symptoms rejected significantly more ambiguous  offers than any other subgroup, suggesting impaired emotion regulation in those with ADHD and aggressive CD. Correlations within the CD group showed that the rejection rate to moderately unfair offers was predicted by aggressive CD symptom severity, but not callous and unemotional traits. These findings highlight the fact that ADHD is a heterogeneous condition from an emotion regulation point of view.Although attention-deficit hyperactivity disorder (ADHD) has been linked to emotion dysregulation, few studies have experimentally investigated this whilst controlling for the effects of comorbid conduct disorder (CD). Economic decision-making games that assess how individuals respond to offers varying in fairness have been used to study emotion regulation. The present study compared adolescent boys with ADHD ( It has long been recognized that children with attention deficit hyperactivity disorder (ADHD) have difficulty regulating their emotions. In particular, research has shown that children with this disorder exhibit greater emotional reactivity , higher In the early conceptualisation of ADHD, emotion dysregulation was considered a cardinal symptom . It was et al. )Most individuals experience a negative emotional response and increased arousal when receiving unfair offers , and a net al. [The rejection of unfair offers has been found to be associated with activity in neural substrates involved in negative emotions, such as the amygdala  and anteet al.  found siet al.  showed tThe results of studies in children and adults assessing emotion regulation suggest that age is an important factor. It is consistently found that adolescents reject more unfair offers than younger children and adults ,49,50, sWhen assessing the contributory effects of comorbid externalizing disorders, it is important to consider the clinical and aetiological heterogeneity of disorders, such as CD and ODD ; not allet al.’s [Callous-unemotional traits (CU) are another potentially important source of heterogeneity when looking at externalizing disorders. Such personality traits identify those at greater risk for severe antisocial behaviour  and reduet al.’s  study ofet al.’s  and adolet al.’s  or betweet al.’s .Only a few studies have examined emotion regulation using the UG in adolescents ,49,50,58Participants were recruited from the Child and Adolescent Mental Health Services and Community Child Health Clinics in Wales. Children in the sample were of British Caucasian origin and met research criteria for a lifetime diagnosis of ADHD. Children with any known clinical or research diagnosis of schizophrenia, bipolar disorder, autistic spectrum disorder (ASD), Tourette’s syndrome or with an IQ < 70, epilepsy, brain damage or any other neurological or genetic disorder were excluded from the study. In total, 204 adolescent males with ADHD  took part in the present study. No participants were stimulant naive, but participants who were currently being prescribed stimulant medication were asked to come off their medication at least 24 h prior to testing.N = 47) were recruited from local comprehensive schools and youth centres from relatively deprived areas in Cardiff. The Youth Self Report , aged 13–18  was usert  and theEthical approval was obtained from the Wales Multicentre Research Ethics Committee. Informed written consent was obtained for all accompanying parents and adolescents aged over 16 years. Written assent was obtained for younger adolescents.Child psychopathology was assessed using the Development and Well Being Assessment (DAWBA) structured interview using both parents and children as informants . ParentsODD has previously been viewed as being part of a CD diagnostic spectrum. It is characterised as a less severe form of CD, which is often a developmental precursor to CD . HoweverCU traits were measured using the Youth Psychopathic traits Inventory . The CUParent-rated emotional symptoms were assessed using the Strengths and Difficulties Questionnaire . This wCognitive ability was re-assessed on all current participants using the Wechsler Abbreviated Scale of Intelligence , 2-subseIn the Ultimatum Game , two plaet al. (2003) asked participants to rate what offers they considered to be fair, irrespective of whether they decided to reject or accept an offer. Of their participants, 58% considered any offer less than 5/5 as unfair, with the remaining 42% deeming anything less than 7/3 to be unfair. Therefore, although 100% of the participants deemed the offers of 8/2 and 9/1 unfair, participants were divided with respect to the fairness of the 6/4 and 7/3 offers. For these reasons, the offers were grouped into three groups: truly fair (5/5), very unfair (8/2 and 9/1) and moderately unfair (7/3 and 6/4).Offers made were either 5/5 , 6/4 , 7/3 , 8/2  or 9/1 . Participants were the responders in a series of 22 trials, in which they saw a photograph of a different person during each trial who made them an offer. In accordance with Koenigs and Tranel’s  paper, op < 0.05). Ten participants had an estimated IQ < 70 and were excluded. Therefore, 184 ADHD participants were included in the analysis, as well as 47 control participants referred to as normal controls (NC). The ADHD group consisted of those with ADHD only . Those with additional CD  were split into those with low aggressive CD symptoms  and high aggressive CD symptoms (ADHD + CD/HA n = 30), based on whether they were below or above the mean (mean = 3.33 symptoms). Between-subject ANOVAs were used to test differences in offers and acceptance rates between groups. Offers were grouped into three offer types: completely fair (5/5), moderately fair (6/4 and 7/3) and highly unfair (8/2 and 9/1). Because the UG variables were not normally distributed, follow up Bonferroni pairwise comparisons were bootstrapped and reported with 95% confidence intervals. Non-parametric Kruskal-Wallis tests were also conducted and found the same results.Effect sizes are reported as partial eta squared . AnomalThe demographic data for the two subgroups and the results of between-group analyses are presented in There was no difference between the three clinical groups in ADHD severity or the emotion subscale of the SDQ. There was also no significant difference between the CD groups for CU traits and ODD symptoms, but these groups were significantly higher than the ADHD-only group.F = 1.48, p = 0.22, ηp2 = 0.02.First, the original proposed offers were compared see . A betweF = 0.53, p = 0.66, ηp2 = 0.01) nor highly unfair offers  = 2.36, p = 0.07, ηp2 = 0.03). However, the groups did differ significantly in acceptance rates for the moderately unfair offers  = 3.07, p = 0.03, pη2 = 0.04), and this remained significant after controlling for age and IQ (p = 0.03). The results of nonparametric Kruskal-Wallis tests confirmed these results: proposed offer, χ2 = 2.16, p = 0.54; fair offers, χ2 = 0.59, p = 0.90; moderately unfair offers, χ2 = 9.39, p = 0.03; highly unfair offers, χ2 = 2.43, p = 0.49. Follow-up bootstrapped pairwise comparisons showed that this effect was driven by the ADHD + CD/HA group rejecting significantly more offers than the other three groups .We then compared the acceptance rates for the different offer types between the groups see . BetweenDue to the difference found between the two CD groups, we wanted to explore the variation in symptoms between them. As shown in F = 5.11, p = 0.026, R = 0.23. Total CD score did not enter into the equation at Step 2 of the analysis .A stepwise multiple regression was then conducted to evaluate whether both aggressive CD and total CD scores predicted the acceptance of moderately unfair offers. At Step 1 of the analysis, the aggressive CD score entered into the regression equation and was significantly negatively related to acceptance rates: This study sought to examine whether ADHD adolescents in general have a problem with emotion regulation or whether this is a specific problem in those with conduct disorder, especially those with predominantly aggressive symptoms. No study until now has examined economic decision-making using the UG in a clinical sample of youths with ADHD, with or without CD. This study supports previous work  suggestiUnsurprisingly, the vast majority of the adolescents accepted the fair offers and rejected the unfair offers. Generally our adolescent male groups accepted fewer unfair offers than those reported for adults ,39. ThisFollow-up tests showed that the ADHD with aggressive CD group rejected significantly more moderately unfair offers than any other group. Previous studies claim that the rejection of unfair offers is due to anger and a desire to punish the opponent, and the responder’s ability to regulate anger and frustration therefore plays a critical role in task performance . All thrThe results suggest that ADHD alone is not associated with emotion dysregulation during the UG compared to normal adolescents, supporting the view that emotion dysregulation is not a core feature of ADHD. The fact that the biggest difference between groups was between the two CD groups highlights the importance of treating CD as a heterogeneous disorder. The results showed that aggressive symptoms predicted performance on the UG better than overall CD severity, supporting the idea that aggressive antisocial behaviour has a different aetiology than non-aggressive behaviour ,54.In the present study, participants were told that the aim of the game was to gain as many points as possible. Apart from this, there was no other incentive for them to win. The use of real reward incentives might, therefore, have a large impact on the rate of offers accepted. Further research is needed to help determine this in order to facilitate the development of more specific interventions for CD. For example, intervention programmes may be more beneficial by focusing on emotion regulation management in individuals with aggressive CD, whilst working with incentive-based goals in individuals with low-aggressive CD.et al. [i.e., whether the proposer had a fair or unfair alternative offer to choose from), whereas offenders low in psychopathy did not, suggesting stronger impairments in social decision-making. However, even if similar behaviour patterns are shown in high and low psychopathy scorers, these might represent different motivations, as suggested by recent imaging studies [et al. [n = 6) and lack of a non-ASB control sample, further research is needed. Our groups did not differ significantly in internalising emotionality (measured by the SDQ), and it may be the case that the low anxiety component of psychopathy drives regulation problems. Further research is needed using a clinical sample of children with disruptive behaviour problems, and improvements could be made by using a combination of parent, teacher and behavioural observation to assess CU traits, as suggested by the new CU specifier for the CD diagnosis in the DSM-5.Unlike aggression, CU traits did not influence the acceptance of offers, supporting previous studies, which found no significant difference between individuals scoring high or low in psychopathy ,58,59, b studies ,58, and  [et al.  observedAn issue that needs further exploration is the assumption that the acceptance of unfair offers is the rational decision. From an economic perspective, the rejection of offers is irrational, because it results in a personal loss. However, from a social perspective, rejection of unfair offers can be seen as a rational, altruistic action to preserve social norms. Rather than maximizing self-interest, the participant chooses to punish the socially-inappropriate action from the proposer for the good of the general population ,74. ThisAnother limitation of the study is that during the UG task, no direct measure of participants’ emotional responses, such as psychophysiological recordings or subjective ratings, were obtained. Because we did not measure participants’ emotional response to offers, we do not know how much participants needed to self-regulate. One would assume that the more intense the shift in emotion, the more regulatory resources would be needed in order to modify that emotion. It is difficult, however, to determine from this study whether the boys with aggressive CD had deficient regulatory resources or experienced a more intense emotional reaction. Previous findings of reduced psychophysiological responding to aversive stimuli in the sample group would suggest the former ,82. Futui.e., temperamental or biological factors) lead children to demonstrate impairing levels of emotional dysregulation. Furthermore, existing treatments need to be modified to address the role of emotional regulation in children with ADHD. They should incorporate cognitive-behavioural techniques to teach emotion recognition and physiological relaxation exercises for negative emotions [Emotion dysregulation is a dimensional trait that is not unique to ADHD. It is important to uncover to what extent individuals with ADHD and comorbid CD develop emotion regulation deficits for reasons that are different from those with CD alone by testing psychopathology in non-ADHD samples. Longitudinal studies are needed in order to define how the developmental trajectories interact with one another, to see, for example, whether emotion regulation difficulties bridge the development of aggressive behaviour in children and adolescents with ADHD or whether factors underlying both ADHD and comorbid aggressive CD (emotions ,84 and eemotions .In conclusion, this study of adolescent boys with ADHD and controls found a significant difference in the acceptance rate of ambiguously unfair offers of boys with ADHD and highly aggressive CD. The results suggest that it is the subgroup of boys with both ADHD and predominantly aggressive CD that has difficulty with emotion regulation, which causes them to make more “irrational” decisions. Importantly, boys with ADHD alone did not differ from controls in performance on the decision-making task. Further research is needed to better understand how emotion regulation influences decision-making and antisocial behaviour in the short and long term amongst adolescents, including those with psychiatric disorder.


Guidelines in the United Kingdom recommend that medication titration for attention deficit hyperactivity disorder (ADHD) should be completed within 4-6 weeks and include regular reviews. However, most clinicians think that weekly clinic contact is infeasible, and audits have shown that this timeline is rarely achieved. Thus, a more effective monitoring and review system is needed; remote monitoring technology (RMT) may be one way to improve current practice. However, little is known about whether patients with ADHD, their families, and clinicians would be interested in using RMT.To explore patients’, parents’, and health care professionals’ views and attitudes toward using digital technology for remote monitoring during titration for ADHD.This was a qualitative study, and data were collected through 11 focus groups with adults and young people with ADHD, parents of children with ADHD, and health care professionals (N=59).All participant groups were positive about using RMT in the treatment of ADHD, but they were also aware of barriers to its use, especially around access to technology and integrating RMT into clinical care. They identified that RMT had the most potential for use in the ongoing management and support of ADHD, rather than during the distinct titration period. Participants identified features of RMT that could improve the quality of consultations and support greater self-management.RMT has the potential to augment support and care for ADHD, but it needs to go beyond the titration period and offer more to patients and families than monitoring through outcome measures. Developing and evaluating an mHealth app that incorporates the key features identified by end users is required. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by 3 core behaviors—inattention, hyperactivity, and impulsivity—and affects approximately 5% of school-aged children . Left unDevelopments of eMental Health for ADHD include digital and Web-based psychometric tools ; behavioInternet availability and mobile devices are now within the reach of most of the population, enabling new systems of health monitoring to be considered without the previous problem of excluding large sections of the population. In the United Kingdom, 85% of all adults have household access to the Internet, and this rises to 94% among 16-24 year olds; furthermore, mobile Internet appears to have the fastest growing audience (an increase of 11% from 27.2 million unique users in March 2103 to 30.2 million by March 2014) . By MarcIn the United Kingdom, an identified unmet need in ADHD treatment is the delay in reaching the optimum dose for patients commencing medication . During initial medication titration, the National Institute for Health and Care Excellence (NICE) ADHD Guideline  highlighRemote monitoring technology (RMT) is a means of collecting physiological or health-related data from individuals passively or by their active input on an electronic device, such as a mobile phone, and relaying these data over an internet or phone connection to a remote server. Given the ubiquity of mobile device use and Internet availability in the population, the conditions for using RMT as an adjunct to traditional models of service delivery appear better than ever. Using RMT offers a potential solution to delays in titration currently experienced in the NHS. However, little is known about whether patients and health care professionals in the NHS context would support the introduction of RMT to aid treatment monitoring for ADHD. Moreover, there is a need to ensure the quality of any RMT products and that patient and families’ needs remain at the center of any technology development and implementation . TherefoWe conducted an exploratory cross-sectional focus group study with patients, parents, and health professionals. Focus groups were chosen as the preferred method of data collection for this study because they enable an exploration of experiences and views and facilitate discussion between participants on a topic of shared interest . The setThe prototype RMT enabled automated text messages to be sent to patients who were invited to complete Web-based versions of routine outcome measures (ROMs) to monitor symptoms and side effects. The system comprised a clinician dashboard where patient details were entered and the specific ROMs required for each individual patient were selected. The dashboard indicated when patients had completed their measures and showed red flags for any issues of concern. To use the RMT patients required a mobile phone to receive text messages and activate the links to the Web-based versions of the ROM. Once completed, the data were relayed back to the system server and the clinician dashboard updated. The primary aim of the prototype was to enable the clinic to receive information about responses to and side effects of medication during the titration period in addition to that obtained from face-to-face appointments. Screenshots of the prototype are displayed in Before undertaking the focus groups, a workshop was held to elicit feedback on the prototype RMT system from potential end-users. It was attended by a young person with ADHD and his parent, 2 adults with ADHD, 1 psychiatrist, 1 psychologist, and 1 medical technology researcher. This workshop identified key factors to explore in more detail in the focus groups. The experience of the workshop suggested that demonstrating the prototype system during the focus groups would risk diverting attention away from the primary research purpose. This was primarily because the “on-boarding” process for the prototype RMT was lengthy—individual patient details needed to be entered into the clinician dashboard and patients needed to both receive and reply to SMS text messages. In the short time we had available in the scheduled focus groups, we determined that this process would dominate the session and limit the time needed for exploring participants’ views and acceptability of the general concept of RMT. Therefore, we decided not to use the prototype RMT in the focus groups, but instead created printed materials from the system to aid in discussion see -3.The study sample comprised 8 young people with ADHD (YP), 11 adults with ADHD (adults), 9 parents of children with ADHD (parents), and 31 health care professionals (HCP) working with people with ADHD see . YP, aduInclusion criteria were a self-reported diagnosis of ADHD or having a child with a self-reported diagnosis of ADHD. This was checked by asking participants to confirm where they had received the diagnosis . HCPs were recruited by the local investigators at each NHS provider organization. The criterion for inclusion was employment in a service treating people with ADHD. A purposive sample of HCPs was sought to reflect the range of staff involved in medication management in clinical settings and implementation of any new systems.Eleven separate focus groups took place in areas with variable relative deprivation including inner cities, post-industrial towns, and semi-rural districts. They were held in locations convenient to the participants (either NHS clinic or support group premises) and took place between June and September 2014. Each group was limited to a single participant type see  18] and and18] aThe study received ethical approval from the UK National Research Ethics Service Committee South Central - Berkshire B (ref 13/SC/0641). Information about the study was sent to all potential participants before the scheduled focus group date. At the beginning of each session, the study was explained to participants and any questions were answered. All adult participants gave their written informed consent to take part. Parents of the YP aged under 16 gave their written informed consent for their children to take part, while the YP gave their verbal assent. YP, adults, and parents were all given a £20 shopping voucher as a reward for their participation. HCPs all took part during their usual working times, so no remuneration was given to them.Each focus group was facilitated by 2 members of the research team. One member brought domain (insider) knowledge about ADHD (ZY), while the other brought methodological (outsider) knowledge about focus groups (LS or MC). The facilitators sought to remain “background figures”  in the gThe discussions were guided by a topic schedule covering 4 key areas: using technology for health; medication titration experience/practice; remote monitoring for effects and side effects; and aspirations for using technology to manage ADHD see . DrawingP<.001). Once all of the data were organized into the refined coding frame, members of the wider research team  engaged in detailed discussions, which led to the identification of overarching, interpretative themes. These themes aimed to capture the essence and strength of the participants’ experiences and views; by assigning individual codes to these themes, we were able to maintain a close fit between the data and the more abstract, interpretative themes. Theme-level matrixes ” was key to their diagnosis, as opposed to being “fobbed off,” “labeled lazy and idle,” or “[labeled as] naughty.” The difficulties in access to diagnosis, treatment, and support appeared to eclipse the experience of medication titration. By the point of diagnosis and commencing medication, adults and parents were so relieved to have access to treatment and support that the time needed to reach the optimum dose of medication was of less importance to them. This experience was supported by comments from some HCPs, as well.Despite the primary focus of this study being the use of RMT during the titration period, the focus group discussions were dominated by issues relating to access to diagnosis, treatment, and support, especially for adults and parents. Participants recalled the “My cases are usually diagnosed in adolescence so they have been waiting for their ADHD to be treated for years, so a few more weeks [for titration] is not a big deal. The important thing is that the process has started.HCP, Site 1Although there were some examples of positive experiences, most parents and adults highlighted substantial organizational and logistical issues regarding access to treatment; in particular, they cited long waiting times, brief appointments, lengthy intervals between appointments, inconsistent doctors, unpredictable communication, and frequent cancellations.“I’m getting down, I’m not coping. I feel like I’ve been left on my own a bit really” . In addition to support for side effects and symptoms, participants expressed the need for “reassurance” , “someone there if you have a problem” , and “information from someone who “gets it” more than professionals do” .Both parent and adult groups expressed a need for further support. One adult specifically reported As described above, there was widespread use of Internet-enabled mobile devices, computers, and game consoles across the sample, but their use in relation to ADHD was fairly limited. With the exception of YP, all other groups reported using websites for ADHD information. Parents, adults, and HCPs were cautious about Web information; they wanted to access (or recommend) only trusted or reputable websites. A small number of participants used existing generic mobile phone functions to support daily activities . HCPs described how they sometimes recommended general relaxation and meditation apps, rather than apps specifically designed for people with ADHD.However, across the whole sample, there were highly positive attitudes toward the potential for RMT to play a greater role in the management of ADHD. Many participants reported that it could improve communication with the clinic; furthermore, participants across all groups saw its potential to (a) improve the quality of the clinic appointments/consultations and (b) support greater patient self-management.Parents, adults, and HCPs thought that using RMT would save time in clinic appointments by enabling a quicker review of the patient’s recent history and thereby swifter identification of what matters most to the patient/parent.This way you can look back over the previous 4 weeks or 3 months and focus on questions such as—“you scored sleep a 2 here, what was happening at the time that made it so unsettled?” It should help parents to be more productive in giving the information we need.HCP, Site 3Participants also thought that data collected contemporaneously, rather than retrospectively, would not be biased by patient recall and selective memory.Participants saw the potential for RMT to provide the ability to easily monitor symptoms, chart them over time, and identify any patterns or unusual behaviors. This would increase people’s knowledge, self-awareness, and understanding of and confidence in dealing with their condition. All of the groups also saw the potential for RMT to offer personalized feedback in response to patient-entered data. This could be used for reassurance, to avoid unnecessary contact with the clinic, and for motivating feedback to reinforce positive behaviors.It could be a bar with red at the bottom and green at the top and a little person and after each check-up, it moves up or down to show how well you are doing so it gives you the opportunity to realize and change it.YP, Site 3Sometimes I think I’m doing well for a few weeks, then I look back and realize I wasn’t. Something to help me accurately monitor that. That in itself would be an aid to the medication… so you can look back and see what you’ve done well and what things you need to concentrate on doing better.Adult, Site 2While participants broadly welcomed the concept of RMT, specific feedback on the prototype pointed to some important limitations in this approach. For YP, adults, and parents, the prototype did not allow them to retain and use their own (or the child’s) data, and therefore was unable to realize their vision of its supporting greater self-management described above. For HCPs, the primary issue was that the prototype was perceived as onerous to use and difficult to incorporate into current workflows . They emphasized the need for an RMT that saves clinician time rather than adds to it by requiring additional management outside of the current electronic patient record.The barriers and limitations to using RMT were highlighted in all focus groups, although HCPs foresaw more barriers than did parents, YP, or adults.Although most participants used Internet-enabled mobile devices, they thought that other people might have had difficulties in physically accessing the technology or having the necessary skills to use it. This included access to mobile devices, especially ones that would support any new app/software ; access to phones when at school (YP); access to wireless Internet in different locations (YP and HCPs); and capability for interoperability with NHS hardware (HCPs).“adds to what’s there already...not if it’s used as an excuse to see people less” . HCPs were keen on receiving digital information that coincided with patients’ appointments, but noted that “if you start getting notifications about patients from another area clinic it will take up too much time” , and stressed that all of their time spent dealing with digital data be accounted for and appropriately factored into the provider contract. Confidentiality of personal data and privacy was discussed by several groups, as was the need to consider information governance problems and to protect young people from any harms arising from digital tools.RMT was seen as a positive addition to the clinical process only if it Some HCPs and adults were concerned with providing information digitally to clinics, as it may not be responded to promptly, whereas a phone call would be more likely to elicit a response. Others felt this could be useful information, as long as it was understood that the information might not be seen immediately and that patients should be directed to alternative sources of support when needed.“challenging… and funny” . Taken together, the feedback on the prototype RMT and their views on an ideal app points toward a preference for RMT to be controlled by patients, rather than clinics. Four primary functions were identified: organizational aid; a digital coach or mentor; reliable, trustworthy, and tailored information; and symptom or side effect monitoring.Participants across all groups were keen to imagine and discuss the functions of their ideal mobile phone app for ADHD. There were similarities across groups regarding the proposed primary functions as well as the preference for personalization, regarding both users’ ability to control settings and to receive tailored responses. YP also wanted any tool intended for daily use to be Organization aids were frequently mentioned in all groups, apart from YP. For example, 1 HCP thought that a reminder system would be useful:The difficulties I come across, [are that] young people are on medication and they tend to run out at the end of the month and their behavior will go sky high, and it will take them a week to get all the medication back into their system. I think it would be really useful if somewhere in the app, say when they’re...near the end [they receive a message saying] “You need to put in a request for repeat prescription.”HCP, Site 3“something that helps you keep on task and achieve goals...incorporating pre-set plans and lists of tasks” . Another discussed the utility of a timing app:Parents supported this idea, especially as YP begin taking more responsibility for managing their ADHD. Adults wanted support with day-to-day tasks: To figure out how long it takes you to do certain daily tasks eg, showering. The app could then tell you what time you would need to get up to get everything done .“coach” , such as providing supportive statements and motivation:Adults, YP, and HCPs identified potential features that could act as a virtual [It] could have some information based on how long the process should take with messages such as “you may not be seeing any improvements yet, but stick with it”... or you could have messages to parents, such as “Derek might be struggling this week”HCP, Site 3“I’m feeling dizzy—[the] advice would be to go to see your GP” .All participant groups suggested that the app should provide reliable and precise information, based on both personal experiences and professional knowledge. Information about medications was in particular sought by adults, while parents and HCPs wanted links to reputable sites and resources, including existing apps and support groups; YP wanted information about ADHD books. HCPs suggested that an app could give proactive advice about behavior, sleep, and diet. They also felt advice should be targeted with frequently asked questions and specific, tailored responses, such as There was strong support across all groups to track information visually, such as using a graph to illustrate changes in symptoms, side effects, and behavior over time. YP suggested that monitoring mood swings and side effects might be useful. HCPs wanted the ability to monitor medication compliance and side effects, as well as tracking behaviors such as eating, sleeping, and drug and alcohol use during titration. The usefulness of being able to link this information with life events was also identified:Graphs would be useful for example for... patients who stop taking meds but parents and teachers say they have improved. It might help to have the parent and teacher graphs to see.HPC, Site 4Adults wanted the mode of recording information to be tailored to individual preferences, for example, using smiley faces to record mood, using the voice recorder, and linking with other apps such as work calendars. HCPs felt it would be useful if school staff could provide feedback through the app. Parents were happy for YP to enter their own data when they were mature enough, but also wanted to provide feedback and report how they themselves are doing.The participants in this study reflect current trends in technology use ,13, partFirst, while our initial interest in conducting this study was to explore how RMT could improve titration management, and even though our findings support audit work suggesting that the NICE guidelines are not currently met in NHS services  by Hall, 2015), few participants identified this as an area of high unmet need. The exploratory nature of the study enabled new ideas to emerge that moved us beyond titration. Through participants’ detailed accounts, we identified 3 clear phases of living with ADHD: initial assessment and diagnosis; starting treatment (including medication titration); and ongoing support and management. The group discussions with adults, YP, and parents were dominated by their experience of the first phase—namely, trying to access services and getting a formal diagnosis, as described in our second theme . This adds to previous evidence of this being an area of high unmet need , as was Second, participants identified that RMT’s greatest potential was in improving ongoing support and management of ADHD. The use of RMT to improve ADHD by continuing the health care interventions between appointments has previously been recognized . In thisWhile there have been calls for increased use of ROMs and clinical measures to enhance clinical practice , there aParticipants in this study demonstrated a preference for an RMT system that supports greater self-management—namely, one that is patient-owned and controlled, such that patients/parents can choose when and how to use it and specifically when to share the information with their clinician. The widespread adoption of mobile phones and tablet computers in the population makes them advantageous over other digital devices as they are very portable and frequently in the owner’s possession throughout the day . These dAlthough there are some ADHD-specific mobile phone apps available, we are not aware of any evaluations or evidence of their clinical benefit. Research has shown that using generic mobile phone features such as calendars, task lists, and notes, with the support of a human online coach, can be effective in managing ADHD symptoms . ExtendiOur study has demonstrated the vital importance of developing systems in collaboration with the end users. The next stage of research and development for RMT for ADHD will be to adopt well-established user-centered approaches with rapid, iterative cycles of requirements elicitation, design, testing, and redesign . The finGreater patient activation, including self-management and self-monitoring, is a goal for many long-term conditions, not only ADHD. The primary findings from this study—that RMT has a place throughout the patient’s journey (not only targeted at a single stage) and the overwhelming preference for patient-controlled, rather than clinic-controlled systems—may also apply across other neurodevelopmental and mental health disorders. Our use of the HCP sample in this study adds support to this point, as they came from CAMHS and pediatric services where they would treat a range of different conditions. However, it will be important to test these assumptions with other populations; in particular, the detailed user requirements for an ADHD-focused RMT may not transfer directly to other conditions and populations.By engaging with a range of participants, we have explored the commonalities and differences across the key stakeholder groups. We found universal support for technology innovation across these groups and identified their preferences for how this could be implemented. Diversity with respect to gender, age, and ethnicity across our sample was limited, meaning that we may have missed some important perspectives. However, it should be noted that the ethnic profile of our sample reflects previous findings of studies of access to care, where white children were twice as likely as access services than were children from other ethnic groups .By using a defined prototype as a discussion vehicle for RMT within a defined clinical condition, we may have narrowed the scope of the discussion and the ideas of what would be useful or possible. For example, while access to diagnosis was identified as the most significant unmet need, participants’ aspirations for technological support focused on treatment and support. However, many of the ideas proposed diverged from the specific approach taken with the prototype, suggesting that participants had clear ideas for when and how technology would be helpful to them.The findings from this study strongly suggest that YP, parents, and adults with ADHD are looking for a more personalized, responsive approach to ADHD treatment and support in the long term. Patients and their families want more targeted information at a time they need it most, to have control over interventions including medication, to have facilities to record and monitor personal and sensitive information about themselves, and to have support in developing personal strategies that fit with their lives. This study of patients’, parents’, and HCPs’ views of using RMT for ADHD leads us to the conclusion that a technology-based personalized approach for living with ADHD, driven by user requirements, is required. However, implementing RMT requires a key change in the philosophy of health care from routinized clinic-centered care to personalized patient-centered care.


Bartonella species are blood-borne, re-emerging organisms, capable of causing prolonged infection with diverse disease manifestations, from asymptomatic bacteremia to chronic debilitating disease and death. This pathogen can survive for over a month in stored blood. However, its prevalence among blood donors is unknown, and screening of blood supplies for this pathogen is not routinely performed. We investigated Bartonella spp. prevalence in 500 blood donors from Campinas, Brazil, based on a cross-sectional design. Blood samples were inoculated into an enrichment liquid growth medium and sub-inoculated onto blood agar. Liquid culture samples and Gram-negative isolates were tested using a genus specific ITS PCR with amplicons sequenced for species identification. Bartonella henselae and Bartonella quintana antibodies were assayed by indirect immunofluorescence. B. henselae was isolated from six donors (1.2%). Sixteen donors (3.2%) were Bartonella-PCR positive after culture in liquid or on solid media, with 15 donors infected with B. henselae and one donor infected with Bartonella clarridgeiae. Antibodies against B. henselae or B. quintana were found in 16% and 32% of 500 blood donors, respectively. Serology was not associated with infection, with only three of 16 Bartonella-infected subjects seropositive for B. henselae or B. quintana. Bartonella DNA was present in the bloodstream of approximately one out of 30 donors from a major blood bank in South America. Negative serology does not rule out Bartonella spp. infection in healthy subjects. Using a combination of liquid and solid cultures, PCR, and DNA sequencing, this study documents for the first time that Bartonella spp. bacteremia occurs in asymptomatic blood donors. Our findings support further evaluation of Bartonella spp. transmission which can occur through blood transfusions. Bartonella is a genus of small bacteria with worldwide distribution, transmitted by blood-sucking insects, and is capable of causing disease in humans and animals. Some of the clinical presentations of Bartonella spp., such as cat scratch disease, trench fever, and bacillary angiomatosis are well documented; however, novel presentations have been described in the last two decades, ranging from cyclic flu-like syndrome to neurologic disease and life-threatening endocarditis. Asymptomatic human infection is possible and accidental blood transmission has been reported. Bacterium isolation is very difficult because they grow slowly and require special culture media and procedures. Serology testing poorly predicts active Bartonella infection, except in infection of cardiac valves. Therefore, diagnosis is generally challenging. However, when molecular detection techniques are coupled with special culture protocols, enhanced sensitivity and specificity can be achieved. We investigated Bartonella spp. infection prevalence in a large blood donor population and confirmed bacteremia in 1.2% of the subjects. Bloodstream infection was detected with at least three different molecular methods in 3.2% of donors. These results indicate that Bartonella is a genus of importance for transfusion medicine. Bartonella, a genus of fastidious bacteria with worldwide distribution, is responsible for persistent infections in animals and humans [Bartonella spp. are considered neglected zoonotic pathogens, presumed to be transmitted to humans by a variety of arthropod vectors including sandflies, body lice, fleas, ticks, and keds [Bartonella spp., has widened substantially [Bartonella spp. are known causative agents of Peruvian bartonellosis, cat scratch disease, trench fever, and bacillary angiomatosis [Bartonella sp. infection among differential diagnoses [d humans . Bartoneand keds ,2. Durinantially . In humaomatosis . Howeveromatosis ,5. With iagnoses .Bartonella spp. are able to infect and survive inside erythrocytes [In vitro, these bacteria have been shown to invade, multiply within, and persist for the lifetime of the infected host cell [Bartonella spp. have been associated with human infections, B. henselae is the most frequent species identified from humans, as well as from companion animals such as cats and dogs [hrocytes , resultihrocytes . In vitrost cell ,10. Proland dogs . There iand dogs ,11.B. henselae to survive in stored blood for 35 days, suggesting the potential for transfusion-associated transmission [B. henselae adhered to human erythrocytes 10 hours after inoculation of the bacteria into blood and intraerythrocytic infection after 72 hours [Bartonella sp. in transfusion medicine, particularly as blood transfusion infection has been documented in cats [Bartonella sp. has also been reported in two veterinarians [Bartonella spp. was previously documented in blood samples of asymptomatic subjects [Bartonella sp. occurs in blood donors at the time of donation. The objective of this study was to determine the seroprevalence and frequency of bacteremia caused by Bartonella spp. in a large asymptomatic blood donor population in Campinas, São Paulo State, Brazil.Previous studies by our group using transmission electron microscopy and culture isolation have documented the ability of smission . We also72 hours . These r in cats  and needinarians ,16. Sincsubjects –20, we hth to December 23rd 2009, at the time of their voluntary blood donation. Sample size was estimated in 473 subjects to allow for estimation of at least 5% prevalence of bloodstream infection with Bartonella spp. in blood donors, with a desired precision of 5% given a 95% confidence limit and a design effect of 1. Therefore, with possible attrition, we enrolled 500 donors. This study was approved by the Research Ethics Committee of the University of Campinas (UNICAMP), Brazil (CEP122/2005). An informed written consent, approved by the UNICAMP Research Ethics Committee, was obtained from each participant. Donor selection, blood collection, and infectious disease screening were performed in accordance with current international standards [A cross-sectional study was conducted at the UNICAMP Blood Bank (HEMOCENTRO), which serves a geographic region with an estimated population of 6.4 million people in the São Paulo state, Brazil. Healthy blood donors were randomly recruited from November 19tandards ,22. Follet al. [et al. [Bartonella alpha-Proteobacteria growth medium (BAPGM) [Bartonella spp.-negative sheep blood (confirmed by PCR and culture methods) [Bartonella spp. culture methods were carried out in a class 2 biosafety cabinet in order to minimize the possibility of specimen contamination and to protect laboratory personnel.Culture procedures used in this study followed the previous description by Duncan et al.  and Magg [et al. , with mo (BAPGM) , incubatmethods)  for addimethods) , an initMolecular techniques were performed in four separate rooms to avoid DNA contamination. A uni-directional workflow was strictly enforced between pre-PCR areas  and post-PCR areas . Dedicated sets of equipment, pipettes, and supplies were used in each of these locations. Strict laboratory procedures were implemented in order to avoid potential contamination of reagents and samples with amplicons. In order to prevent PCR contamination, different negative controls testing the different stages in the PCR process was included in every experiment as described in the Bartonella genus-specific single tube PCR. This assay was manually designed to target a hypervariable region of the 16S-23S rRNA gene intergenic transcribed spacer (ITS) of Bartonella species using primers and conditions described in the B. henselae; ATCC 49882). These screening tests were performed at the Multidisciplinary Center of Biological Investigation (CEMIB), UNICAMP, Brazil.After a 14-day incubation period, a 1 mL aliquot of liquid culture medium was centrifuged and the pellet was subjected to DNA extraction using the QIAamp® DNA Mini Kit . The average of DNA yield obtained was 6.19 ng/ul (SD: 32.8 ng/ul), and the average 260/280 ratio was 1.47 (SD: 2.03). Screening of the 500 liquid culture samples was performed using Bartonella sp. positive liquid cultures and DNA from suspected subculture isolates were retested at Western University of Health Sciences, USA, for species identification. These DNA samples were tested by a Real-Time ITS PCR using primers manually designed to amplify a fragment of the 16S-23S rRNA ITS region of all Bartonella species. PCR primers and conditions are described in the DNA obtained from Bartonella sp. DNA were further characterized using previously published conventional PCR assays for the ITS region [gltA) [pap31) gene [Bartonella koehlerae [DNA samples from six isolates that were confirmed to contain S region , for then [gltA) , and the31) gene . In addioehlerae . DNA samB. henselae and B. quintana antigens supplied by the Centers for Disease Control and Prevention , serum samples were analyzed for IgG antibodies to B. henselae and B. quintana antigens by an indirect immunofluorescence assay (IFA) as described in the Using Bartonella sp. bloodstream infection. Molecular and serologic prevalence of Bartonella spp. were described as absolute frequencies, percentages, and 95% confidence intervals (computed using score method) using JMP Pro 10 for Windows .Subjects with positive ITS PCR results from isolates were considered bacteremic. Subjects positive from liquid culture were considered with Bartonella spp. based on culture in liquid and/or isolation on solid media followed by ITS Real-Time and/or conventional PCR in two different laboratories. ITS amplicon sequence analysis revealed B. henselae in 15 of the 16 cultures , and B. clarridgeiae in one culture   subjects were infected with a 0%–1.1%) . Among tirmation . Only onB. henselae sequences deposited in GenBank (accession number NC_005956.1). From one liquid culture sample, a 190 bp ITS DNA sequence was obtained, being 100% similar to B. clarridgeiae (accession number NC_014932.1). Similarly, the presence of B. henselae DNA was confirmed in five isolates by also amplifying and sequencing the gltA gene , and from three by amplification and sequencing of the pap31 gene . By testing the isolates, no blood donor was B. koehlerae PCR positive using species-specific ITS primers. The methodologies applied in our laboratory allowed the isolation of fastidious bacteria morphologically similar to Bartonella by Gram stain from 34 blood donors, with six isolates confirmed as Bartonella spp. by DNA sequencing. Some of the possible genera of the other isolates obtained in this study include Arthrobacter, Bacillus, Dermabacter, Methylobacterium, Propionibacterium, Pseudomonas, Sphingomonas, Staphylococcus and unknown “non-cultured” bacteria, as previously reported by Cadenas et al. using the same liquid enrichment culture method [When subsequently amplified and sequenced, four of these six isolates contained a larger ITS region fragment (559 bp in size) that was 100% similar to e method .B. henselae or B. quintana were detected in 16.2%  and 32% , respectively. Seropositivity for both antigens was detected in 13.4% of blood donors . B. quintana DNA was not detected in any blood donor in this study. Only two of the B. henselae seroreactive blood donors were confirmed by liquid culture/PCR as infected with B. henselae. However, two B. quintana seroreactive donors had confirmed B. henselae bloodstream infection, one of whom was also seroreactive to B. henselae. The B. clarridgeiae bacteremic subject was seronegative to both Bartonella spp. antigens  of 500 healthy blood donors presented to a major blood bank in Southeastern Brazil. Despite the fact that exposure of blood donors to Bartonella spp. has been previously documented by serology methods [Bartonella spp. in blood donors using similar culture and molecular diagnostic methods. A total of six B. henselae isolates were obtained in this study, with other ten blood donors having blood infection with B. henselae or B. clarridgeiae identified by liquid culture enrichment coupled with DNA amplification by PCR at two different laboratories. These results indicate, for the first time, that asymptomatic blood donors can be infected with Bartonella spp. at the time of blood donation.Using a combination of liquid and solid cultures, PCR, DNA sequencing, and serology, this study documented the presence of  methods ,30, no pBartonella spp. are re-emerging infectious agents that can induce asymptomatic and intraerythrocytic infection in preferred and accidental hosts. These bacteria have been isolated from both immunocompetent and immunodeficient human patients [B. henselae in collected human blood units [patients ,9,31. Anod units  associatod units ,32, and od units ,16, suppBartonella sp. infection [Bartonella sp. bacteremic cats and dogs [Transmission via blood transfusion is of great relevance if the transfused agent subsequently causes short or long-term disease manifestation in the donor recipient. In humans, cat-scratch fever, bacillary angiomatosis and endocarditis are the most common historically recognized disease entities caused by nfection . Howevernfection ,16,33,34and dogs –37.Bartonella sp. is highly fastidious and isolation by direct plating of blood or other clinical samples is not always successful. In order to improve the chances of isolation of Bartonella sp. from blood, samples should be cultured in liquid enrichment media to support growth [Haemophilus influenza and other bacteria species [Bartonella spp. DNA was identified more frequently from BAPGM liquid culture samples than from subculture isolates, with only one subject PCR positive at both culture methods  had BAPGM liquid culture samples positive for Bartonella DNA, but isolates were obtained only from five subjects (4%), including from two patients with PCR-negative liquid culture samples [Bartonella spp. in the bloodstream of these infected blood donors was not determined. Low bacterial burden in the bloodstream may limit the transmission of Bartonella spp. to a blood recipient or the development of infection. In addition, the discrepancy between the number of Bartonella sp. isolates obtained and the number of BAPGM samples positive by PCR could indicate that PCR-positive BAPGM samples contained non-viable bacteria. However, the two culture systems used in this study were designed to reproduce the vector environment (insect-based liquid culture medium BAPGM) and the host environment (blood-enriched agar medium), and each culture system may have facilitated the growth and detection of specific wild types of Bartonella. Consequently, the use of a combined diagnostic platform for testing the presence of Bartonella spp. DNA in BAPGM liquid culture and in subculture isolates in this study provided enhanced sensitivity, as previously demonstrated [Diagnosis of bartonellosis remains a microbiological challenge because of the difficulty of culturing and isolating the bacterium from patient specimens. t growth , similar species . In our  methods . Similar samples . In this USA, 48 % had BAPBartonella sp. infection may be confirmed by microbiological isolation, molecular techniques, and histopathologic visualization of Bartonella sp. antigens from tissue samples. Serology can be used to document exposure, but does not confirm infection. In this study, antibodies against B. quintana or B. henselae were detected in 32% (136/500) and 16.2% (78/500), respectively. A previous Brazilian study involving 437 healthy subjects from a rural area of Minas Gerais state documented B. quintana and B. henselae seroprevalences of 12.8% and 13.7%, respectively [Bartonella spp. seroprevalence among 498 blood donors was 16.1%, but only 1.2% of those subjects were seropositive for B. henselae [B. henselae [Bartonella sp. correlated poorly with infection as detected by PCR amplification followed by DNA sequencing or with the successful isolation of Bartonella organisms. Similar findings have been previously demonstrated in animals [Bartonella serodiagnosis are exemplified in the study by Vermeulen et al. [Bartonella spp. manipulate the host immune system on a systemic scale to achieve a state of immunological attenuation, including stimulation of IL-10 secretion, which suppresses the capabilities of various immune cells, including T helper cells, monocytes/macrophages, and dendritic cells, thus interfering with both innate and adaptive immune responses [Bartonella spp. infection in asymptomatic donors is low, supporting the recommendation that antibody status should not be used as a sole diagnostic modality to determine Bartonella spp. infection in blood donors. Moreover, negative results in one or more currently available diagnostic tests cannot exclude infection and, whenever possible, a combination of diagnostic tests is encouraged [Evidence of ectively . In Swedhenselae . In New henselae . In our  animals ,41 and hd 16.2% 7/500, resd 16.2% 7/500, res animals . Difficun et al. . It is scouraged ,43.Bartonella spp. is the development of diagnostic techniques with improved sensitivity [Bartonella sp. gene targets, following extraction of DNA from patient blood samples, does not rule out this bloodstream infection. It is estimated that Bartonella bacteremia in asymptomatic donors is approximately 10 CFU/mL of blood [Bartonella spp. typically cause a cyclic bacteremia [Bartonella sp. infection in humans is improved when three sequential blood samples are tested during a one-week period [Bartonella sp. bloodstream infection were documented as positive on more than one sample test date and no patient was positive on liquid culture/PCR for all three specimen test dates. Therefore, the number of bacteremic subjects may be underestimated in our study because only one blood sample from each blood donor was tested. We hypothesize that the actual number of blood donors infected with a Bartonella spp. may be higher in healthy humans than our current findings have documented. The low bacterial levels and the cyclic feature of Bartonella sp. bloodstream infection reinforce this hypothesis [Another factor related to the apparent emergence of sitivity . In recesitivity ,8,11,26.cteremia . It has k period . In thatpothesis ,10.Bartonella sp. positive blood donors in this study were considered inappropriate for further blood donations. To the authors’ knowledge, there are no specific guidelines in the USA or other countries designed to prevent transfusion of human blood when donors are suspected to be infected with a Bartonella species. In Veterinary Medicine, at least two major medical boards have issued recommendations regarding blood donors. In 2005, the American College of Veterinary Internal Medicine (ACVIM) conditionally recommended the screening of canine and feline blood donors in order to obtain a Bartonella-free donor pool, especially for cats due to the high frequency of bacteremia in this host [Bartonella-free blood products for transfusion to immune suppressed subjects, which would include pediatric and geriatric patients.Based on recommendations by the Ethics Committee from UNICAMP Medical School, his host . This rehis host . The resBartonella spp. frequently occurs in the Southeast region of Brazil, and that Bartonella sp. bacteremia occurs in asymptomatic blood donors. There is a risk of blood supply contamination with these pathogens from asymptomatic bacteremic donors. The impact of transmission of Bartonella spp. through blood transfusions recipients should be evaluated, as well as the use of advanced diagnostic techniques for the screening of Bartonella sp. infection among blood donors.The results of this study indicate that human exposure to S1 Appendix(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


Deficits in impulsivity and affect dysregulation are key features of attention-deficit/hyperactivity disorder (ADHD) besides impairing levels of hyperactivity and/or inattention. However, the neural substrates underlying these traits are relatively under-investigated. In this study, we use resting-state functional magnetic resonance imaging to test the hypothesis of diminished functional integration within the affective/limbic network  of children with ADHD, which is associated with their behavioral measures of emotional control deficits. Resting state-fMRI data were obtained from 12 healthy control subjects and 15 children with ADHD, all who had a minimum one-month washout period for medications and supplements. Children with ADHD demonstrated less integrated affective network, evidenced by increased bilateral amygdalar and decreased left orbitofrontal connectivity within the affective network compared to healthy controls. The hyper-connectivity at the left amygdalar within the affective network was associated with increased aggressiveness and conduct problems, as well as decline in functioning in children with ADHD. Similar findings in affective network dysconnectivity were replicated in a subset of children with ADHD three months later. Our findings of divergent changes in amygdala and orbitofrontal intrinsic connectivity support the hypothesis of an impaired functional integration within the affective network in childhood ADHD. Larger prospective studies of the intrinsic affective network in ADHD are required, which may provide further insight on the biological mechanisms of emotional control deficits observed in ADHD. Affect dysregulation is a key feature of attention-deficit/hyperactivity disorder (ADHD) in children ,2. AlthoAbnormalities in large-scale, distributed brain networks are now widely thought to underlie the core features of mental disorders, including ADHD ,10. An ia priori. The RS-fMRI measures of other regions, typically whole brain, are then correlated with the seed RS-fMRI measures to obtain a functional connectivity map of the seed [Two distinct methodological approaches are widely used to analyze RS-fMRI measures. The first approach is region-of-interest (ROI) or “seed”-based. It is a hypothesis-driven as one or two ROI/seeds are chosen the seed ,19. The the seed . It is dthe seed ,20. The the seed –24. Othethe seed  and amplEmerging RS-fMRI studies of ADHD have shown abnormalities in large-scale resting-state networks such as the frontoparietal, dorsal attention and default mode networks, which are associated with ADHD-related behaviors of impaired executive control, lack of attention, and mind-wandering ,24,26–29Three recent seed-based RS-fMRI studies of ADHD—one conducted in the adult cohort and the other two in the child cohort, have examined components of the intrinsic affective network ,40. HypeIn this study, we hypothesized a divergent, less integrated affective network  in children with ADHD, as compared to healthy controls. We predicted that the altered affective functional connectivity in ADHD is associated with behavioral measures of emotional control dysregulation. To complement the prior seed-based findings of the affective network in ADHD, we adopted a data-driven approach (ICA) to measure the functional connectivity within the affective network. This approach is independent of the seed definition and automatically removes motion and physiological noise . The spaThe investigation was carried out in accordance with the guidelines of the Institutional Review Board for the National Healthcare Group, the Singapore Health Services Group and National University of Singapore. Written informed consent from the parents and assent forms from the child to partake in the studies and to allow imaging data for further analyses were both obtained after the nature of the procedures had been fully explained.19 children with ADHD were recruited at the Child Guidance Clinic, Institute of Mental Health. The subjects with ADHD were diagnosed by child psychiatrists according to the Diagnostic and Statistical Manual-Fourth Edition (DSM-IV) for ADHD. Additionally, parents were also interviewed using the Diagnostic Interview Schedule for Children (DISC), which is based on DSM-IV. The subjects with ADHD were either the inattentive or combined subtypes. 3 of the subjects with ADHD had a comorbidity of either developmental dyslexia and/or developmental reading disorder. Prior to the study, 3 subjects with ADHD were on methylphenidate and 5 subjects were taking fatty acid supplementation. They were only allowed to participate in study procedures after at least one month of washout. The rest of the subjects were medication naive. MRI scans from a subset of the subjects with ADHD (11 out of 19) were additionally collected three months later. Throughout this period, these follow-up subjects remained medication and supplementation free. 16 demographically-matched healthy controls were recruited via advertisements from both the Child Guidance Clinic and National University of Singapore. The controls had no present or history of mental disorders. Exclusion criteria for all subjects included history of epileptic seizures, mental retardation and an IQ of less than 70.Neuropsychological assessments were administered on children with ADHD at baseline. No assessments were performed on healthy subjects or the children with ADHD at follow-up. The rating instruments used in this study are the Child Behavior Checklist-Parents (CBCL)  and ChilAdditionally, as a marker of deficient emotional self-regulation (CBCL-DESR) in ADHD , t-score2, voxel size = 3.0 mm isotropic, slice thickness = 3 mm, no gap, 36 axial slices, interleaved collection) were collected while the subjects were asked to relax and stare at a cross centered on a screen. The RS-fMRI data collection  was broken up into two consecutive short runs to minimize motion artifacts; the duration for each of the two runs were 4 min 6 seconds each. An eye tracker was used to ensure that the children stayed awake for the entire RS-fMRI scan. The high-resolution structural T1-weighted magnetization prepared rapid gradient echo images  were collected for atlas registration of the RS-fMRI images, as well as for subsequent structural analysis of voxel-based morphometry (VBM). After three months, an additional set of the same scans was collected from a subset of children with ADHD on the same scanner.All functional and structural images were collected at the Duke-National University of Singapore Graduate Medical School as part of a multi-modal imaging protocol using a 12-channel phase-array head coil on a 3-Tesla Tim Trio scanner . The RS-fMRI data using T2*-weighted echo planar images  [The structural T1-weighted MRI data of all subjects passed the visual check for motion artifacts. VBM was performed for each subject using SPM8  ,. Grey me/spm8/) . The reshttp://mialab.mrn.org/software/). To extract the spatial pattern of the affective network from each individual, the following steps were performed: 1) concatenating the preprocessed data of 2 runs of 4 min 6s for each subject across groups, 2) combining the data across all groups  into an aggregate dataset, 2) using principal component analysis to perform initial reduction of random variables, 3) extracting thirty group-level independent components using minimum description length criteria, with reference to previous studies [The pre-processed the RS-fMRI signals were decomponsed into spatially independent components using open-source Group ICA Toolbox  v studies , 5) back studies .Demographic and clinical differences between the groups  were tested using either two-tailed independent sample t-tests  or chi-squared tests .p < .05. To compare the affective network connectivity between the subjects with ADHD and healthy subjects, two-sample t-tests with the same regressors were performed. Following our previous work [http://www.gin.cnrs.fr/) was used to identify the specific brain region showing group-wise functional connectivity differences within the affective network. The MarsBar toolbox (http://marsbar.sourceforge.net/) was used to extract the subject-level mean affective network connectivity in the above regions with group-wise differences.To examine the validity of the affective networks identified in both datasets, group-level average functional connectivity map of the affective network were created using one-sample t-test across the individual spatial maps of the affective network (both controls and ADHD) , regressous work , we idenous work . The staTo examine whether the group differences in functional connectivity of the affective network could be explained by the underlying grey matter volume, we performed the voxelwise grey matter volume correction following our previous method . The Biop < .05. Additional clinical correlations were performed with scores on the CBCL-DESR, as well as the Child Global Assessment Scale. Furthermore, we conducted similar post-hoc correlational analyses on 10 subjects with the combined subtype of ADHD (hyperactive-impulsive and inattention), excluding 5 inattentive subtype ADHD subjects.To examine whether there was a relationship between behavioral constructs of affect problems in the 15 subjects with ADHD and the region displaying group-wise differences, post-hoc Pearson correlational analysis was performed on the six CBCL subscales. Multiple comparisons were performed using the Bonferroni-Holm method to control for Type 1 errors at a FWE  or dataset 2 (Table 2). The brain structures of the affective network identified by ICA were namely the amygdala, anterior hippocampus, parahippocampal gyrus, basal forebrain , subgenual anterior cingulate cortex, ventromedial prefrontal cortex subsuming the orbitofrontal cortex, anterior insula and cerebellum .There were no significant differences in the demographic variables and imaging variables  between the ADHD cohort and healthy controls in either dataset 1 . The findings of increased left amygdalar  and marginally decreased left orbitofrontal  connectivity were replicated in a subset of ADHD subjects three months later .Compared to healthy subjects, children with ADHD in dataset 1 displayed greater left and right amygdala , peak z-score of 3.20; and right: 28, -1, -13; cluster of 177 voxels (p = .009), peak z-score of 3.68) and decreased left orbitofrontal , peak z-score of 3.98) connectivity within the affective network , peak z-score of 3.15; right amygdala: cluster of 160 voxels (p = .005), peak z-score of 4.03; and left orbitofrontal cortex: cluster of 216 voxels (p = .002), peak z-score of 3.94). The same was observed for the subset of ADHD after three months.Post-hoc correlations in dataset 1 revealed that the increase in left amygdalar connectivity significantly correlated with measures of conduct problems   and aggrPost-hoc analysis of ten children with ADHD with combined subtypes (i.e. excluding five subjects with inattention subtypes) compared to healthy controls, revealed enhanced significant associations between increased amygdalar connectivity and increased emotional control problems  after multiple comparisons. Significant positive association with the CBCL-DESR  and negative association with the global function  were also found in children with ADHD-combined subtype.We present evidence of abnormal affective network connectivity in children with ADHD. Compared to healthy controls, children with ADHD displayed reduced orbitofrontal connectivity and heightened amygdalar connectivity within the affective network. Critically, these intrinsic connectivity changes in ADHD remained after three months. The heightened amygdalar connectivity in children with ADHD significantly correlated with emotional dysregulation problems and a decline in general functioning. Our findings suggest a less integrated affective intrinsic network in children with ADHD that might underlie their emotional dysfunction.Previous seed-based studies of the affective network have found mixed results of hyper-connected and hypo-connected affective network in ADHD ,39,40. OThe abnormal affective networks in ADHD children may underlie parts of their behavioral problems. One study has shown that the hypoconnectivity between the left orbitofrontal cortex and left ventral striatum of the affective network correlated with the emotional lability measures in medication naïve children with ADHD . AnotherTill date, the neurobiological substrates of intrinsic functional connectivity are not yet known. Although structural deficits in grey matter of the limbic regions in children and adults with ADHD have been previously reported ,68, our Non-human primate evidence suggests that intrinsic functional connectivity correspond to direct and indirect anatomical connections . By usinThe divergent patterns of hypoconnectivity of the orbitofrontal cortex and hyperconnectivity of the amygdala in our findings correspond to the findings of hypoactivation of the orbitofrontal cortex and hyperactivation of the amygdala in many emotional task-based fMRI studies in ADHD ,28,35–38The strengths of our study included a minimum one-month washout period for methylphenidate and fatty acid supplementation  ,75, and In conclusion, our study supports the hypothesis that the affective network connectivity is abnormal in children with ADHD. Given that frontolimbic dysfunction continues till adulthood in ADHD ,77,78 an


Considerable overlap in diagnostic criteria and shared psychopathologic symptoms in attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) have stimulated research activities in this field. Longitudinal studies have shown that BPD is frequently diagnosed in adult patients who had been diagnosed with ADHD in childhood. The question of whether ADHD and BPD randomly co-occur as comorbidities, have similar origins or share common pathological mechanisms remains unresolved. Some authors suggest that ADHD contributes to the development of BPD via various mechanisms, and therefore consider it a risk factor for later BPD development.In this article the evidence for the co-occurrence of these disorders will be reviewed as well as studies on their common genetic and environmental influences. Temperamental and developmental issues will be reviewed, and shared features such as impulsivity and emotion dysregulation discussed. From a therapeutic perspective, few studies have investigated psychotherapeutic treatment of the comorbid condition, though the issue is highly important to the management of patients suffering from both disorders. Some thought is given to how therapeutic methods and approaches can be modified to benefit patients, and to their possible succession. In recent years, shared symptoms and considerable overlap in clinical presentation between attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) have stimulated research activities in this field. Since the 1980s numerous studies have furnished evidence on the persistence of ADHD symptoms in adulthood . ADHD syOn the one hand, since the publication of the Wender Utah Criteria  emotion Discussion is continuing on whether ADHD and BPD occasionally co-occur as comorbidities and have common origins, possibly with ADHD traits being the precursor of later BPD, or share common pathological mechanisms. Against this background there has been discussion about which therapeutic approach would be the most beneficial, even if research activities in this field are still scarce.This article gives an overview of current knowledge about the close links, subtle distinctions and significant differences between the two disorders. It deals with different aspects of the association between ADHD and BPD, taking into account possible common origins in neurobiology and inborn temperament as well as common mechanisms concerning neuropsychology and emotion regulation. As we consider this a very important issue to improve and broaden knowledge of therapeutic options for patients with both ADHD and BPD, this basic information is provided as a starting point for clinicians dealing with patients suffering from both conditions. The article will also give some thought to therapeutic aspects and formulate some tentative recommendations.Marked tendency to act unexpectedly and without consideration of the consequences,To engage in quarrelsome behavior and to have conflicts with others, especially when impulsive acts are thwarted or criticized,Liability to outbursts of anger or violence, with inability to control the resulting behavioral explosions,Difficulty in maintaining any course of action that offers no immediate reward andUnstable and capricious  moodBPD is classified as a personality disorder (PD). The DSM-V defines the main features of BPD as a “pattern of instability in interpersonal relationships, self-image, and affects, and marked impulsivity” . ADHD acDifficulty waiting his or her term (e. g. while waiting in a line)Blurting out answers before a question has been completed or blurting out inappropriate comments without regard to consequences andInterrupting or intruding on othersThe criteria of the impulsivity domain in ADHD according to the DSM-V are quite similar (see the criteria of the impulsivity domain of ADHD according to DSM-V):Affective lability or mood shiftsHot temper outbursts or short-lived explosive outbursts or constant irritability andEmotional over reactivity in the sense of over reactivity to routine life stressBecause of this apparent overlap the phenomenological differentiation between “borderline-impulsivity” and “ADHD-impulsivity” is merely possible from a clinical viewpoint. Both patient groups often seem to act without taking into consideration the consequences of their behavior. According to the ICD definition of the impulsive subtype of emotionally instable PD, the cited impulsivity criteria also comprise emotion control/regulation difficulties (outbursts of anger). The aspect of emotion dysregulation was added to the definition of adult ADHD when the Wender-Utah criteria were published. Wender et al. proposed a set of characteristics :to specify current ADHD symptoms in adults which are not only based on the behavioral criteria outlined in DSM-V, but also comprise associated features and subjective symptoms .Thus, it is evident that there is a descriptive overlap with the affective instability domain in BPD. Wender’s proposal has been tested, and evidence has emerged to affirm that in adult ADHD there is an elevated risk for deficient emotional self-regulation (DESR) , 17–19. The considerable overlap between symptoms of ADHD and BPD in the core domains of impulsivity and emotional dysregulation led to the idea that both disorders might be the result of different developmental pathways based on common underlying pathologic mechanisms and differing in symptom severity .Psychopathological presentation was therefore investigated in adult patients with ADHD compared to BPD patients and control subjects with a focus on Borderline symptomatology . SeveritGiven the similarities in symptom presentation, one might think that ADHD and BPD are different modes of the same disorder. However, states of inner tension  which arWe searched relevant registers for studies on ADHD. Furthermore, we screened the reference lists of relevant articles manually. Included were papers in English, German and French. Studies of any design focusing on ADHD and BPD were screened and categorized. We used the categories research on comorbidity, etiopathology, temperament and development, neuropsychology and treatment to summarize the findings.A search for studies dealing with ADHD and BPD was conducted for the following bibliographic databases: Pubmed, Embase, Medline, PsychInfo, Central . The following terms were used: (ADHD OR (attention deficit) OR (attention-deficit) OR hyperactivity*) AND  OR borderline*). The search included all fields in Pubmed, Embase, Medline and PsychInfo databases and abstract, title and keywords in the Central bibliography : 11660, Medline (ME95) see Pubmed, Psychinfo 418, Central  19, NCBI webside 420).By 1979, a connection between minimal brain dysfunction and BPD was assumed to exist . InvestiIn adult ADHD, PDs are frequent comorbidities , 29. JacThe association between ADHD and BPD has been primarily studied on a phenotypic level. Recently a study investigated the genetic and environmental contributions to this association using a dimensional approach. Borderline personality traits and ADHD symptoms were assessed in a sample of 7233 twins and siblings from the Netherlands. The phenotypic correlation between ADHD and BPD symptoms was high (r = 0.59) and was the same for both genders. According to the authors, 49% of the high phenotypic correlation can be explained by genetic influences and 51% by environmental factors . It seemTo study environmental influences on ADHD symptoms, Lehn and colleagues conducted a longitudinal study in monozygotic twins . Twins wOther environmental risk factors that contribute to or influence the development of BPD include traumatic experiences. It has been found that the lifetime prevalence of Posttraumatic Stress Disorder (PTSD) and BPD in a nationally representative sample of the U. S. population is 6.6% and 5.9% respectively  Wave II, N = 34.653, ). PTSD aA recently published large longitudinal study followed children with and without ADHD and their siblings for 10 years (mean age at follow-up: 22 years). This study revealed that ADHD was an independent risk factor for later PTSD with an OR of 2.23 . RucklidPredictive data concerning the development of BPD comes from prospective studies. Burke and Stepp, for example, report on longitudinal data from a clinical sample of 177 boys, first diagnosed at ages 7 to 12 and followed up annually to age 18 and reassessed at age 24 . DiagnosA study of 103 female adult patients meeting DSM-IV criteria for ADHD or BPD used a latent class analysis (LCA) and identified four subgroups. Hyperactivity was present in all four subgroups and thus does not discriminate between ADHD and BPD. Developmental pathways were also investigated. One possible pathway leads from combined ADHD symptoms or mainly inattention symptoms in childhood to an adult profile containing only symptoms of ADHD and not BPD. Another possible pathway leads from a childhood profile with low levels of hyperactive/impulsive symptoms but no inattention problems to an adult profile with symptoms of BPD . TemperaOf the official diagnostic criteria defining ADHD and BPD, the highest overlap between the two disorders seems to be in the domain of impulsivity. But what is meant by impulsivity? A comprehensive definition of impulsivity does not exist. The presentation of impulsive behaviour is manifold, and comprises behaviours that often result in undesirable outcomes because they are not sufficiently thought-out or inappropriate or occur in an untimely fashion –53. ImpuMoreover, Krause-Utz and colleagues reported stress-dependent increase in state impulsivity in patients with BPD  in comparison to an ADHD only group and healthy controls . BPD seeAs emotion dysregulation is often considered the core feature of borderline psychopathology, components of emotion dysregulation have been intensively studied in BPD (for Review see ). EvidenIn ADHD research evidence in the field of emotional dysregulation is relatively sparse. Negative emotions seem to contribute to or aggravate ADHD symptoms , 81 via It can be assumed that individuals suffering from ADHD, easily overwhelmed by emotions, might struggle with emotional regulation strategies designed to suppress the expression of emotion. Evidence comes from a study of boys suffering from ADHD compared to a control group. Both groups were observed during a frustrating competitive Puzzle Task and randomised to direct instruction to either control their emotional expressions or let them run their natural course. The ADHD group was not as successful in doing so as the control sample. In the ADHD group the difference in emotional dysregulation between the condition instructed to control their emotions and the natural course condition was not as pronounced as in the control group. The effect of suppression on the level of emotional dysregulation in ADHD children was rather small, which points to the conclusion that ADHD children are less effective in suppressing their emotional expressions .It is currently not possible to compare emotion regulation in BPD and adult ADHD because more evidence for its role in ADHD is required, and no direct comparison studies have been carried out Table In clinical practice, ADHD may frequently be missed in patients with a diagnosis of BPD. As ADHD is a frequent comorbidity in BPD and entails additional problems and impairing consequences in daily life, in therapeutic contexts careful diagnostic assessment of symptoms and problems is necessary. In each individual patient a decision about the necessity of treating the ADHD symptoms needs to be made based on a balanced evaluation of the severity of impairments due to ADHD, the patient’s resources, compensatory strategies and the patient’s demands . FrequenADHD in adults can be treated effectively with stimulant medication and atomoxetine. International guidelines propose methylphenidate (MPH) as the first line treatment in adult ADHD –91. MPH Case-reports of successful methylphenidate treatment in patients with co-morbid BPD and ADHD have been published , 94. GolIt can be assumed that BPD patients suffering from ADHD are hindered in the accomplishment of psychotherapeutic steps because ADHD implicates difficulties in planning, structuring, concentrating, arranging timetables and pursuing schemes. Motivation is often fragile, initial enthusiasm is followed by frustration and boredom, and focusing on central themes often remains a challenge. To avoid early discontinuation of treatment and disappointment, ADHD should be kept in mind and included in the planning of treatment steps.BPD traits  and BPD For adults with ADHD a number of different psychotherapeutic programs are available, mostly group therapies (for Review see –108). AnPsychoeducation on both disorders and treatment options;Pharmacological treatment of ADHD symptoms if their severity indicates a treatment and if psychotherapeutic approaches might be facilitated by treating ADHD conditioned impairments. Stimulants are the treatment of choice for adults with ADHD, with long-lasting, extended release formulations preferred to avoid rebound with the risk of enhancement of mood swings and dysfunctional behavior, and for protection against abuse ;Coaching on ADHD related therapy-interfering behaviors ;Individual psychotherapy and/or group therapy with the aim to improve behavioral, social and functional impairments; andLong-term follow-up to avoid early discontinuation and repeated disappointing experiences.A systematic approach to treatment can be proposed, including:There has been little scientific research on systematic treatment approaches for comorbid patients suffering from BPD and ADHD, and more research in this area is needed.ADHD and BPD share some clinical features, particularly impulsivity and emotional instability. These disorders often co-occur. Patients with both diagnoses have more pronounced difficulties which are intertwined and often difficult to treat. In particular, impulsivity seems to be a severely impairing characteristic of patients suffering from both disorders. In BPD, impulsivity is primarily driven by affective and interpersonally sensitive aspects. In ADHD, deficits in attentional and cognitive processing account for behavior inhibition problems, referred to as impulsivity. Systematic treatment programs for patients with both ADHD and BPD are lacking, and there is a need for more research in this area. To stimulate research in the field of co-morbid ADHD and BPD we consider it important to further address the questions of gene-environment interactions, vulnerability to emotional neglect and abuse, and to broaden knowledge about temperament and the risk for traumatic experiences. Future research on impulsivity should include direct comparisons between ADHD, BPD and comorbid ADHD + BPD groups. The field of emotion regulation research in ADHD needs to be expanded to better understand interrelations between executive function deficits as well as (under-)stimulation and emotion regulation. The family interactions between parents and children with ADHD need to be considered from an emotion regulation perspective. Treatment options for comorbid patients suffering from ADHD and BPD should be developed and evaluated. Current knowledge emphasizes that therapeutic approaches need to take both disorders into consideration. Moreover, therapeutic planning needs to carefully consider symptom domains and selection of therapeutic steps and their succession.