The review examines Attention Deficit Hyperactivity Disorder (ADHD in its Child and Adult form) and its various presentations  with a particular focus on environmental , lifestyles and comorbidities. It is argued that ADHD is best understood in a holistic and interactive context and a vast empirical literature is presented to illustrate the point: Environmental factors include stress in general as well as exposure to toxins . Social factors are illustrated by effects of social deprivation and seduction to unhealthy lifestyles. Maternal lifestyle during pregnancy is pointed out , which all tend to be related to ADHD. Family environment is discussed with respect to protective effect of (mainly authoritative and autocratic) parenting styles. Societal factors include mainly economic and political issues: income inequality and poverty (low SES is an ADHD risk factor) and a growing moral dilemma between a humanistic effort to globally spread the knowledge of ADHD and the medicalization and commercialization of the disorder. The second part of the review is devoted to ADHD related lifestyles and resulting comorbidities . Although ADHD is a neurodevelopmental disorder, its assessment and treatment are also linked to environmental, behavioral and social factors and their interactions. Attention Deficit Hyperactivity Disorder (ADHD) is a lifelong neurodevelopmental disorder marked by its observable behavioral manifestations. The continuum of the symptoms is not always clear and ADHD may or may not continue into adulthood. The disorder presents itself as ‘childhood ADHD’ and ‘adult ADHD,’ with childhood ADHD being more common . The disThe marked symptoms of ADHD include general inattention, hyperactivity, impulsivity, and difficulty in self-control. These are seen in the various presentations of the disorder and they are divided in what was once called subtypes of the disorder but are currently referred to as presentations; they are ‘Hyperactive Impulsive’ (ADHD-HI) ‘Inattentive’ (ADHD-I), and ‘Combined’ (ADHD-C) . ImportaThere is a general agreement that the disorder disproportionately affects males compared to females but the gender proportion greatly differs among different studies; e.g., Data from 2007 relevant to ADHD worldwide found childhood ADHD to be around 5.3% with lower rates in lower income nations and 3.4% incidence for Adult ADHD. The authors emphasized the importance of studying Adult ADHD to a greater extent, as this was before the DSM-5 classification . The proAttention Deficit Hyperactivity Disorder is considered the most genetically anchored mental disorder  with prolifestyles, a concept which is familiar to medical experts (cf. widely publicized lifestyles of cardiovascular or diabetic patients) and at the same time comprehensible to the general public. We perceive lifestyles as key in the presentation of ADHD, its management and to a great degree also significant in the instigation of ADHD. We define lifestyle in terms of distinct behavioral patterns. Curiously, one of the best fitting definitions of lifestyle can be found in the We focus specifically on Modern science tends to consider phenomena in larger micro or macro contexts. In case of ADHD it became quite logical to focus at the microlevel of the phenomenon and a great progress is being made, e.g., in microanatomy. However, the larger social and environmental contexts of ADHD tend to be underestimated or ignored. The venture of this review is to reveal the lesser known ADHD contexts.A growing body of literature indicates a relationship between ADHD and environmental, social, and societal factors. The three types of factors differ by their nature and links to ADHD but they cannot be viewed separately as they are naturally intertwined with each other. For example, all of these factors can become a source of stress and exposure to stress hormones  and thus causally related to later ADHD . The intExposure to environmental toxins and industrial additives have a potential negative influence on the development of the nervous system. Maleficial chemical agents and pollutants can affect the developing fetus in the maternal womb; babies are later further affected by contaminated nursing bottles, pacifiers and toys and other plastic products for daily use.Phthalates are very common as they make plastic more flexible, thus they are found in children toys, medical devices as well as in cosmetics. In animal studies exposure to these chemicals has been found to induce hormonal disturbances and developmental symptoms of hyperactivity very similar to human ADHD . Animal Bisphenol A (BPA) is ubiquitous in food packaging and other plastic products. This chemical has received media attention due to its correlation with insulin dysfunction and its mild oestrogenic effects that can influence development–especially intrauterine and fetal development. Most recently, the discovery that BPA directly influences the dopaminergic system during early development is especially relevant to ADHD and other disorders marked by impulsivity , where the child is not being properly taken care of and the parents are often missing from the households . A systeOne of the most classically acclaimed examples is the Strict authoritarian parenting as well as negligent parenting were the most widely implicated parenting styles associated with drug and alcohol abuse . A CanadStudies looking into the parenting behaviors of adults with ADHD found significant differences in self-reports and observations about their own relationship and parental style with their children. ADHD Inattentive parents were most likely to self-report negative parenting, as they were consistently ignoring their children and getting easily annoyed with them. In the Hyperactive Impulsive group much more positive interactions were observed, in the self-report ADHD parents had a tendency to conflate their positive parenting to higher self-esteem or a result of exaggeration due to other comorbid mental illnesses often seen in ADHD-HI like Antisocial Personality Disorder .The family is the most influential environment where children’s behavior is influenced and habits are formed . A functWhile suffering from ADHD appears as a highly individualized private matter, the intervening factors may be of a general societal nature. Poverty and lack of access to resources are at the forefront of societal phenomena quoted in the literature.Lower SES and trends toward non-traditional single parent households  have beeStill, the issue of poverty, status and ADHD is not without controversy. While ADHD does typically correlate with low SES, some perceive an opposite tendency: ADHD appears to be almost a fashionable, trendy label in advanced societies. It is most prevalent in the USA and Western Europe, much less so in developing countries. The rest of the world is trying to catch up with the United States; e.g., a noted sociologist, P. Conrad–was quoted by the Huffington Post article by The question still remains to what degree the poor economic status is the result of societal factors  or the result of parents’ mental health, genetic factors and others. A consensus tends to be in a conclusion that multiple factors are important at the same time . ExtensiLifestyles related to ADHD are easily acquired within the family as social learning would entail. A longitudinal study on ADHD found low SES to be one of the greatest risk factors for ADHD. Furthermore, this was associated with parental behaviors that are easily learned such as higher rates of smoking and eating junk food as a normal staple food . In a crIn summary, it is important to keep a holistic point of view and not to underestimate the extrinsic factors influencing this disorder such as SES and the effect of certain lifestyles mothers had before the individual was born.The above mentioned effects are all significant and at times preventable but it is important to keep in mind that these lifestyles and higher exposure to toxic chemicals and pollution are also generally associated with lower SES and the social problems that are associated with poverty  which wiAttention Deficit Hyperactivity Disorder is associated with various peculiarities in lifestyle and resulting comorbidities which vary with the different manifestations of the disorder and present themselves in various developmental stages of life. The comorbidities are both somatic and/or behavioral, we will focus primarily on those that are related to certain behavioral manifestations associated with the disorder such as addictive gaming and impulsive eating leading to obesity and addiction.From the neonatal stage there is an association between certain particularly irritable temperaments and later negative emotive expression in pre-school. Many of these children are later diagnosed with ADHD .Attention Deficit Hyperactivity Disorder is not a uniform disorder, it consists of three clinical presentations; Hyperactive Impulsive (HI), Inattentive (I), and Combined Hyperactive Inattentive (CHI). The various presentations of ADHD differ in comorbidities . This isThe Inattentive presentation of the disorder showed different comorbidities like depression and anxiety. Furthermore, the individuals showing higher inattentive presentation of the disorder manifested more frequent social isolation and lack of intimate relationships . ObesityNicotinism, alcohol abuse, and drug abuse were all noted pathological lifestyles and comorbidities in the ADHD Hyperactive Impulsive “subtype” as it was defined in the Diagnostic and Statistical Manual of Mental Disorders IV-TR. Perhaps the most serious aspect of ADHD lies in its tendency to be associated with disorders, some of which impact not just behavior but personality. This endangers not just the well-being and life of the ADHD sufferers but also of their social environment. These comorbidities are seen in children and if not resolved by late adolescence can then become personality disorders such as antisocial PD or continue as externalizing disorders into adulthood.In a sample of 358 Australian children diagnosed with ADHD, 92% had other comorbid health conditions along with parents suffering from some disorder . As was Attention Deficit Hyperactivity Disorder is commonly associated with other externalizing disorders . These aSleep disorders are another comorbidity that affect children with ADHD at a much higher level than normally developing children. A meta-analysis review evaluating studies from 1987 to 2008 found consistent differences such as bedtime resistance (defiance to parents), sleep onset difficulties, night awakenings and at times low sleep duration . Other sObesity has been linked with ADHD both in childhood and adulthood in several major longitudinal studies and meta analyses, making it one of the most common comorbidities of ADHD with males being more afflicted with the condition . Incidenp = 0.01). However, the study did not find an association between children with only ADHD and obesity (OR = 0.870). Those with ADHD and not obesity were found to have lower levels of physical activity, furthermore, the study did not differentiate among the clinical presentation of the disorder . After accounting for demographic factors , ADHD patients with comorbid learning disability that were medicated had lower obesity rates than non-medicated patients . This study suggests that ADHD symptoms alone are not associated with obesity, and points toward a different possibility: the presence of other comorbid psychiatric disorders and or social factors. The study supports the lower incidence of obesity in medicated patients, but the length of time of drug treatment or the type of drug used  was not reported  correlate strongly with later obesity . A longiAttention Deficit Hyperactivity Disorder is often associated with substance abuse and addiction. It has been estimated that almost one quarter of those suffering from Substance Use Disorder (SUD) have comorbid ADHD and they furthermore have a much worse prognosis in treatment compared to non-ADHD substance abusers . DiffereA Swiss study found that young adults (mean age of 20) with ADHD and comorbid Antisocial Personality Disorder had been experimenting with legal and illegal drugs from an early age. The study found higher rates of cocaine and nicotine use/addiction, but not as much alcoholism compared to controls .In a Danish longitudinal study looking at gender and its influence on SUD found that unlike in the general population, the rate of individuals with SUD and ADHD was at times higher in females. Different comorbidities were also reported in the female population such as higher rates of depression, pointing out that although ADHD is more common in males than in females, the disorder is just as disruptive in females although it may have a different and more masked presentation . In contSubstance abuse and alcoholism are widely known to be running in families, and research shows both environmental and genetic causes . A meta-Similarly to drug addiction, currently we see more cases of compulsive internet use, social media addiction and video game addiction; we refer to these as the new addictions. A French study tested almost 1000 college students with five assessment inventories including the Wender-Utah, ASRS-V1, UPPS, Rosenberg Scale and CPPG to assess both ADHD in childhood and in adulthood. It revealed that the Adult ADHD Hyperactive Impulsive presentation is highly correlated with problematic gambling and had the highest rates of video game addiction .As with the other lifestyles and comorbidities, there are gender differences in problematic computer use and psychiatric disorders. In some cases, even paradoxical ones, for instance a study in Taiwan looking at which type of ADHD presentation and gender is more likely to show higher rates of internet addiction, found that those with higher inattentive symptoms and females with ADHD were most likely to be addicted to the internet . SubsequSimilarly, Table 1).Attention Deficit Hyperactivity Disorder is a common neurodevelopmental disorder. Our article is devoted to a variety of factors which are involved in its onset and presentations; we paid particular attention to factors of an environmental nature spanning from chemical to societal agents which are often neglected – see (Table 2).Accompanied by behavioral manifestations, lifestyles and comorbidities make the life of the patients and their families difficult. The lifestyles appear both in the role of precursors and symptoms – see  have been consistently shown to greatly contribute to the disorder from the prenatal period on. Adequate communication by clinicians and an awareness of these factors is very important. Pediatricians and General Practitioners should be well aware of the environmental risks to the developing fetus and warn the prospective mothers about preventable hazards.We strongly recommend that new research includes healthy lifestyle, enhancement of family communication, as well as sound societal policies besides inevitable focus on the neurological substance of the disorder. One positive change for educators and schools is to have longer outdoor time for children and emphasize the importance of physical education as this has been very helpful for hyperactive and ADHD children . AdditioSW: Contributed to ideating the review, designed and literature review. RP: Supervised the work contributed to literature review. MK-B: Contributed to literature review. AE and KS: Contributed to literature review and formatting. JR and MG: Contributed to supervision and literature review.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.


The topic of intravenous (IV) fluids may be regarded as “reverse nephrology”, because nephrologists usually treat to remove fluids rather than to infuse them. However, because nephrology is deeply rooted in fluid, electrolyte, and acid-base balance, IV fluids belong in the realm of our specialty. The field of IV fluid therapy is in motion due to the increasing use of balanced crystalloids, partly fueled by the advent of new solutions. This review aims to capture these recent developments by critically evaluating the current evidence base. It will review both indications and complications of IV fluid therapy, including the characteristics of the currently available solutions. It will also cover the use of IV fluids in specific settings such as kidney transplantation and pediatrics. Finally, this review will address the pathogenesis of saline-induced hyperchloremic acidosis, its potential effect on outcomes, and the question if this should lead to a definitive switch to balanced solutions. Crystalloids should be distinguished from colloids, in which—chemically speaking—insoluble particles are suspended, but not in solution. A naturally occurring colloid is albumin, which was first used to treat trauma casualties, including burn patients after the Pearl Harbor attack . Th. Th64].


Attention-deficit/hyperactivity disorder (ADHD) is a complex highly comorbid disorder, which can have a huge impact on those with ADHD, their family, and the community around them. ADHD is currently managed using pharmacological and nonpharmacological interventions. However, with advances in technology and an increase in the use of mobile apps, managing ADHD can be augmented using apps specifically designed for this population. However, little is known regarding the suitability and usability of currently available apps.The aim of this study was to explore the suitability of the top 10 listed apps for children and young people with ADHD and clinicians who work with them. It is hypothesized that mobile apps designed for this population could be more suitably designed for this population.The top 10 listed apps that are specifically targeted toward children and young people with ADHD in the United Kingdom were identified via the Google Play (n=5) and iTunes store (n=5). Interviews were then undertaken with 5 clinicians who specialize in treating this population and 5 children and young people with ADHD themselves, to explore their opinions of the 10 apps identified and what they believe the key components are for apps to be suitable for this population.Five themes emerged from clinician and young people interviews: the accessibility of the technology, the importance of relating to apps, addressing ADHD symptoms and related difficulties, age appropriateness, and app interaction. Three additional themes emerged from the clinician interviews alone: monitoring symptoms, side effects and app effect on relationships, and the impact of common comorbid conditions. The characteristics of the apps did not appear to match well with the views of our sample.These findings suggest that the apps may not be suitable in meeting the complex needs associated with this condition. Further research is required to explore the value of apps for children and young people with ADHD and their families and, in particular, any positive role for apps in the management of ADHD in this age group. A systematic review on how technology can be used to engage this population and how it can be used to help them would be a useful way forward. This could be the platform to begin exploring the use of apps further. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by three core symptoms: inattention, impulsivity, and hyperactivity, which can have a profound impact on the individual, their family, and their community -3. It isXu et al reviewed 19 studies assessing technology use in students with ADHD in the age group of 4 to 19 years. The authors concluded that as yet there is very little evidence to support the effectiveness of such interventions . AnotherAnother study looked at a computer mission game that aims to promote behavioral learning and organization of daily skills such as time management and planning or organizing . ChildreHealth Tracker, has also been used for parents, children, and professionals to track the long-term outcomes of children and young people with ADHD to enable more effective treatments and a more efficient service delivery  should make it so every time you complete one [game level] you get little coins and you can buy backgrounds and that.YP1Another participant noted:It makes you focus on the pattern so you relax.YP2Similarly, clinicians also believed that reward and variety in apps are important to engage the user. One clinician believed that apps for ADHD have the ability to help improve their memory and inhibition impairments, thus targeting the impulsivity in ADHD. It was noted that the apps themselves could be a distraction to other important tasks (n=1):...if they’re rewarded for each activity...they’re going to engage...cos they’re gonna get their dopamine hit each time.HCP4Young people (n=4) and clinicians (n=5) believed that it is important for the apps to be age appropriate for the user. Some participants said that some apps were a bit “babyish,” and some noted that one of the apps was a bit too old for a child because of the language used. One participant noted that one of the apps was describing a scene that was “hard to imagine” (YP1). The participants noted:A bit childish, does it say for 13 [years old]?YP2...I’d rather have it when I’m older.YP4...it doesn’t feel as if it’s aimed at kids.HCP3I think it’s very immature, I dunno what the age range is but it feels like the cartoons I used to watch when I was little *laughs*.HCP5Young people stated that apps must be interactive (n=3). They were less impressed and, at times, frustrated with apps that involved no interaction but simply listening or watching (n=3). They wanted to be involved and interact with the app itself, as noted below:...how I didn’t do anything! This app is fake! Its fake! [the app said he had achieved the next level and he hadn’t done anything].YP3I didn’t like it seriously, it’s mind controlling! .YP5I would like change it a bit so you can like actually do something cos and the moment on the writing you just you don’t...do anything...YP4One clinician also noted that the apps should incorporate learning and make it fun, have a catchy title and app logo, and a simple description. One person highlighted that ADHD medication could affect a child’s ability to engage with an app:Some children who we see with ADHD will be medicated and some won’t and that will affect their levels of concentration...HCP2The following three themes were considered to be important by clinicians but not mirrored by the young people:Clinicians suggested that apps could be used to monitor diet (n=2), a “mood component” , and ADHD symptoms within this population. Some believed they would be useful for keeping a diary (n=3) of these, and one person believed apps would be useful to act as ADHD medication reminders:A child and parent app then the parent can then monitor [ADHD symptoms].HCP1I think something about a diary in terms of perhaps providing prompts or things that they’ve got going on that day...HCP2I think it’s really good to encourage kids with ADHD to monitor the way they feel.HCP3One clinician was mindful that the use of apps could prompt “disharmony” in the home, causing conflict in terms of sharing with siblings (C2). They were also mindful that a number of the apps encourage the user to access them daily. This clinician believed that this could encourage a parent to nag their child to use the app, causing tension in the home as well:...it kind of might at some point cause tension and then, you know disharmony at home and arguments and things like that, prompting them to try and get them to do.HCP2Others believed that as one common difficulty in ADHD is maintaining relationships with friends and family, apps could help facilitate these relationships rather than be harmful to them (n=2):...err I think relationships with peers would be useful...HCP2I think peer relationships would definitely be one thing...if you’re looking at relationships you could also mention family relationships as well.HCP1Additionally, they highlighted that ADHD is a highly comorbid condition and the apps don’t always account for this (n=2). One clinician shared that children with ADHD may have learning difficulties and be behind academically and that some of the apps used appeared challenging for the target age even without the young people having additional needs. One participant stated that autism spectrum disorders are a common ADHD comorbidity and that a symptom of ASD can be the inability to cope with multiple stimuli at once. For example, some of the apps were very visually “busy” with lots of background noise. This clinician described this as “sensory overload” (HCP4); something these users may not always be able to cope with:...a lot of children as you know with ADHD have got autism as well and so sometimes things that are completely too noisy, too bright, unless they pick them, can be a bit of a problem.HCP4This study identified 10 apps that stated they were aimed at children and/or young people with ADHD. Five clinicians working with this population and 5 young people with ADHD were interviewed. Interviews involved sharing the 10 identified apps with participants and asking what they think would make an app suitable for children and young people with ADHD. Young people stated that technology unreliability can be a barrier when trying to engage them with the technology; young people and clinicians believe that the young people want to be able to relate to an app, clinicians wanted apps to target the ADHD symptoms of young people, young people and clinicians wanted apps to provide rewards, and young people wanted to be able to interact with an app. Additionally, 2 clinicians felt apps would be useful to monitor ADHD symptoms, diet, and mood and to improve family and peer relationships.ADHD is a chronic condition with around 60% going on to have some symptoms in adult life . TreatmeIndividuals with ADHD, and especially those with comorbid ASD, often enjoy technology and indeed are skilled with its use. Many apps are advertised for individuals with ADHD and their families ,40,42-44The perspectives of both the clinicians and the young people are needed to build up a full picture. It is important to have the views of clinicians as to whether the apps promote positive behaviors and target specific needs. The views of the young people give guidance as to whether they would actually use the app and whether they found it enjoyable and/or helpful. Individuals with ADHD show most reliable responses to frequent positive reward, so this seems to be a prerequisite of a successful app for the young people themselves.Both clinicians and their patients wanted apps to be technically reliable, to relate in some way to the user, to be age appropriate, and to be interactive. Both were also keen to exploit technology to help them, including, for example, an app to address ADHD symptoms in some way. App developers may advertise their apps to offer what clinicians and young people want, but as yet, there does not seem to be a real evidence base to help families and clinicians decide whether or not an app is likely to work for them. Claims that apps can improve ADHD symptoms need further exploring. Clinical networks and children, young people, and families could work with app developers to trial existing apps and develop new ones.Clinicians also saw the use of apps as a way of collecting data from their patients. For example, some young people do not gain weight on ADHD medications . An app The marketplace for app development and specifically app development in health care continues to expand. It is easy to see that conflict could exist between the desire to make money from an app by producing it in a less-than-ideal way and marketing it quickly and spending time and money researching the benefits of an app. Indeed, once an app has been purchased, the developer may move on to the next project, and families and patients who purchase cheap apps are unlikely to complain if they do not work well for them.There is a need for guidelines and standards for app developers, including a requirement for transparent trials of the usefulness of the app. Clearly, there is however, a balance between making these so time consuming and expensive as to deter developers.To investigate the factors influencing technology acceptance, a model named the technology acceptance model (TAM) provides a basis for attitude measures with two technology acceptance variables: perceived usefulness (PU) and perceived ease of use (PEU) . PU refeFuture research is needed on the value of apps for children and young people with ADHD and their families and, in particular, any positive role for apps in the management of ADHD in this age group. A systematic review on how technology can be used to engage this population and how it can be used to help them would be a useful way forward. This could be the platform to begin exploring the use of apps further.


N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo. The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article.Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis- However, no significant inhibiting effect was proven in a large-scale, double-blind and randomized control study [Intracellular levels of vitamin K and its homologs are significantly lower in most hepatocellular carcinomas (HCCs) as compared with background non-tumor areas ; vitaminin vitro . These fonfirmed ,4,5,6. Tonfirmed ,10,11,12onfirmed ,14. Indeol study . A meta-ol study .N,N-dimethylglycinate hydrochloride (MKH-DMG), the ester derivative of MKH, showed excellent MKH delivery potential regarding the liver without the reductive activation process of MK-4 to MKH [Because the anti-HCC effect of MK-4 may be dependent on the delivery of its metabolite, menahydroquinone-4 (MKH), it is hypothesized that effective delivery of MKH to HCC cells leads to inhibition of HCC proliferation, metastasis and recurrence. However, MKH itself has easily oxidizable characteristics and is unsuitable for clinical use. In our previous studies, menahydroquinone-4 1,4-bis-4 to MKH ,18. To i4 to MKH .The schema for the conversion process associated with the MKH delivery system in HCC cells is shown in MKH-DMG, an MKH prodrug, is hydrolyzed into MKH by esterase after its uptake by cells. GGCX is required for its activity and depends upon MKH, which is generated mainly by vitamin K 2,3-epoxide reductase complex, subunit 1-like 1 (VKORC1L1). VKORC1L1 promotes the reduction of MK-4 to MKH and supports vitamin K hydroquinone-mediated intracellular antioxidation, which is critical for cell survival . In our in vitro. In our cell viability assay, MKH-DMG suppressed the proliferation of HCC cells in a time- and dose-dependent manner both in DCP-positive (PLC/PRF/5 and Hep3B) and DCP-negative (SK-Hep1) cell lines [50 values (14–37 μM) and exhibited 4–18 times stronger proliferation-suppressing activity than MK-4. When cell injury was estimated by LDH release into the medium, no indication of injury was evident during MKH-DMG treatment. MK-4 is usually prescribed at a dose of 45 mg/day (three times per day) with a good long-term safety profile in the treatment of osteoporosis patients. At this dose, the maximum plasma concentration is 1 μM [50 values of MKH-DMG used in the treatment of HCC cell lines may be clinically reasonable levels, and that MKH-DMG is potentially a promising anti-HCC agent available for safe clinical use.MKH-DMG has an inhibitory effect regarding cell proliferation in HCC cell lines ll lines . A rapid is 1 μM ; in a pralues 14– μM and eversus time profile was determined, the AUC0-72 h values for MKH were 3.5–15 times higher after MKH-DMG treatment than those after MK-4 treatment, regardless of whether DCP-positive or DCP-negative cell lines were used. These results indicate that MKH-DMG administration is an effective method for the delivery of MKH to HCC cells.Inhibition of HCC proliferation, metastasis and recurrence by MKH-DMG and MK-4 are determined by their ability to deliver MKH to HCC cells. It is difficult to measure MKH levels accurately in HCC cells because of its highly oxidative characteristics regarding MK-4. However, MKO levels can be substituted for MKH levels . MKH delMKH-DMG as an MKH prodrug shows satisfactory cell-membrane permeability and is effectively hydrolyzed into MKH by esterase present in HCC cells, leading to the rapid and intensive inhibition for HCC proliferation. Perhaps the uptake process for MKH-DMG is different to that for MK-4. Investigation of MKH-DMG uptake including transporter system may be an important target for future research.In a recent investigation, DCP/PIVKA-II was reported to act as a growth and metastasis factor for HCC, and to exacerbate its prognosis . TherefoThe underlying mechanism concerning the effect of MKH-DMG on HCC cell growth suppression should be investigated. Generally, cell-cycle arrest has been considered to be primarily associated with the anti-proliferative action of MK-4 ,11,37,381/S arrest is one of the mechanisms involved in the inhibition of HCC cell proliferation induced by MKH-DMG [in vitro revealed an increase in G1 phase cells and a decrease in S phase cells. In Western blot analysis, the expression of cell cycle-related proteins  decreased and was completely suppressed after 48 h of MKH-DMG treatment in both DCP-positive (PLC/PRF/5 and Hep3B) and DCP-negative (SK-Hep-1) HCC cell lines. Conversely, similar treatment using MK-4 induced only a slight decrease in the levels of these proteins. Additionally, NF-κB was downregulated by MKH-DMG treatment in these HCC cell lines, which might have resulted from effective MKH delivery to the tumor cells using MKH-DMG.In our analysis, it is suggested that G MKH-DMG . Flow cyin vivo [in vivo. Using this MKH delivery system, the effects of MKH-DMG in combating hepatic metastasis and the proliferation of HCC cells (PLC/PRF/5) were examined in a mouse spleen-liver metastasis model (nu/nu mice). Macroscopic findings of liver tumors were estimated at 50 days after transplantation of PLC/PRF/5 cells in MKH-DMG treated and untreated groups. Increases in both liver weight and the percentage of cancer surface area were significantly suppressed in the MKH-DMG treatment group as compared with the untreated group. In the MKH-DMG treatment group, plasma DCP, which is produced by HCC cells, was not detected, although liver metastasis could not be suppressed completely. These findings mean that MKH is definitely delivered to the metastasized HCC cells and that DCP is suppressed by MKH; they suggest the possibility that MKH-DMG could function as an anti-HCC agent in humans. However, subsequent investigation is required to show whether or not a similar effect can be demonstrated after MKH-DMG treatment of human HCC.The clinical benefit of MKH-DMG treatment has been demonstrated using xenografted human HCC cells in vivo . In a prin vitro and in vivo. The anti-HCC effect of MKH-DMG may be the result of cell-cycle arrest with downregulation of NF-κB and cyclin D1 expression. MKH-DMG is a promising new candidate for suppression of the onset of HCC, its recurrence and metastasis without significant adverse effects.The effects of MKH-DMG and MK-4 regarding HCC cells are summarized in


N = 492) and 3 (N = 481) were conducted online and additionally examined whether how participants monitored their progress differed as a function of the domain of the goal . The findings suggest that participants: (i) were less likely to monitor their progress toward goals that were related to avoiding negative outcomes, (ii) were less likely to monitor their progress toward goals related to finances, work, or study with reference to the past, than progress toward other goals , (iii) found it easier to monitor their progress toward goals that they felt confident of attaining, but harder to monitor their progress toward goals related to work or study. Finally, the more participants thought about their goal in quantifiable terms, the more likely they were to monitor their progress, and the easier they found monitoring their progress to be. Taken together, these studies begin to describe the nature of progress monitoring and the factors that influence this important self-regulatory process.Three studies examined how people assess their progress on personal goals , along with factors that might influence the nature of progress monitoring . Study 1 involved semi-structured interviews with 40 participants, in which we examined how participants monitored their progress and whether this was related to: (a) their level of self-efficacy, (b) whether the goal was prevention focused, and (c) whether goal progress was represented in quantifiable terms. Studies 2 ( People often want to know how they are progressing on their personal goals. For example, an employee with the goal to succeed at work might ask her boss for feedback, reflect on whether she is performing better than before, and keep track of whether her deadlines are being met. Theories of goal pursuit such as Control Theory , 1982, SMonitoring goal progress involves comparing the current state with a reference value , 1990. TOne factor that may play a role in monitoring goal progress is whether people think about their progress in quantifiable terms, such as how much weight has been lost , or how many essays have been marked . Progress on some goals, such as having a rewarding relationship, may be more difficult to represent in quantifiable terms. Evidence suggests that people have a tendency to judge their performance based on quantifiable information, even in cases where that information is not diagnostic of the characteristic that they are evaluating  influenced how participants monitored their progress. Finally, Study 3 provided a conceptual replication of Study 2 using multi-item measures.Mage = 32.30 years, SD = 8.74, 28 females) responded and were paid £10 for their participation. Ethical approval for all studies presented in this paper was obtained from the University of Sheffield’s Department of Psychology Ethics Committee.Participants were recruited via an email sent to a list of staff and postgraduate volunteers at a large university in northern England. Forty people  and disagreements were jointly resolved through discussion.Participants were asked how long they had worked on each nominated goal for (in weeks), and why they were pursuing the goal. Responses to the latter question were used to identify whether the goal was: (a) prevention focused, and (b) based on intrinsic motivation. Prevention focused goals were coded as those based on security, responsibility, and/or the avoidance of negative outcomes . Goals were coded as being intrinsically motivated if the person enjoyed performing the activity, and/or because it fulfilled their need for autonomy, competence, and relatedness.Participants were then asked questions about how they monitored their progress toward the target goal. First, they were asked “Do you have an idea of whether you are making progress toward this goal?” Those answering in the affirmative  were then asked “How do you know that you are/are not making progress toward this goal?” Based on each participants’ responses to this question and how they described their goal, we coded whether they represented their progress in quantifiable terms  or not .Participants were then asked: “When people think about their goal progress, sometimes they compare their current situation to the past and sometimes they compare it to a target that they want to meet. So when you think about your progress toward [your goal] do you compare your progress to how you used to [perform on that goal/your previous state], and/or how you would like to [perform on that goal/your desired state]?” Responses to this question were coded as those that involve a comparison to the past , and/or those that involve a comparison to a target . Finally, participants rated how difficult they found monitoring their goal progress  and, as a measure of self-efficacy, how confident they were that they could achieve the goal .M = 141.80 days, SD = 315.28). Participants reported goals for which progress could be easily quantified  and goals for which progress could not be easily quantified (50.4%). About half of the goals were prevention focused, and about a quarter of the goals were based on intrinsic motivation (28.5%). Participants felt moderate levels of self-efficacy . The range of goals that were nominated is presented in the Appendix.Participants described 137 goals in total. There was considerable variation in how long participants had worked on their goals for .Participants sometimes compared their goal progress to a past state  and sometimes to a desired target . Participants considered monitoring goal progress to be moderately difficult  within each participant. Two multilevel logistic regression analyses tested the unique relationships between each predictor  and the outcome variables . A multilevel linear regression with participants’ rating of the difficulty of monitoring progress as a continuous outcome variable was also conducted with the same predictors. SE = 0.42, z = 1.77, p = 0.08). Participants were less likely to assess their goals with reference to a target if their goal was related to security and responsibility  than if it was not. Progress toward goals that were thought of in quantifiable terms were more likely to be compared to a target  than progress toward goals that were not thought of in quantifiable terms. Participants also reported that it was easier to assess their progress on goals for which progress was quantified  and when they felt confident of achieving their goal  .None of the factors were significantly associated with the likelihood that participants reported assessing their progress with respect to the past  was less likely to be compared with a target than if it did not pertain to these factors. This may be because, as One limitation of the approach used in Study 1 is that it required coders to infer how participants construed their goals and how they monitored their progress based on their open ended responses. Therefore, in Study 2 we asked participants to complete an online survey in which they rated aspects of their goals and how they assessed their progress toward them. In addition to the constructs examined in Study 1, Study 2 also examined whether the focal goal’s domain  was associated with the nature of progress monitoring. Instead of asking participants to evaluate their goal and aspects of progress monitoring on binary scales, we used Likert-type scales to increase the sensitivity of our measures. For instance, instead of asking participants if they assessed their progress with reference to past and/or target comparison points, they rated the frequency with which they assessed their progress with reference to past and/or target comparison points.Mage = 33.12, SD = 11.26; 232 females, 261 males, 1 of unspecified gender). It took participants approximately 15 min to complete the survey and they were paid $US0.95 for their time.Five hundred and nineteen participants based in the United States were recruited from the crowdsourcing website Amazon MTurk. To ensure that respondents paid sufficient attention to the questions, we included three test questions that simply asked participants to select a specified response. Twenty-seven participants were excluded for answering at least one of the test questions incorrectly, leaving 492 participants for the analysis  the extent to which their goal was related to security and/or responsibility , (b) involved avoiding a negative outcome , (c) was motivated by intrinsic motivation . Participants also rated their level of self-efficacy using a scale adapted from r = 0.04), and so were retained as separate measures for the analyses . Two independent coders rated whether each goal pertained to physical development or health, finance, work or study, or social relationships. There was a high level of inter-rater reliability , and the goals were dummy coded with respect to the four goal domains  so that they could be entered as predictors into the regression analyses.The two dimensions of prevention focus  were unrelated  progress they are making . They were then asked to rate how difficult it was for them to monitor their goal progress, using the same scale as those used in Study 1 . Next, participants rated the frequency with which they assessed their progress by comparing their current situation to: (a) the past and, (b) a target state that they want to reach (or avoid), on a scale from 1 = never to 5 = almost all the time. Finally, participants rated the extent to which they felt that their goal progress could be quantified, for example, in terms of time, weight, amount, number, frequency, etc. .SD = 46.87). Participants’ goals tended to be more concerned with attaining positive outcomes than preventing negative ones , and were moderately related to security and responsibility . On average, participants reported moderate levels of intrinsic motivation for their goal , and they tended to think about their goal progress in quantifiable terms . Most of the goals that participants reported on related to physical development or health (36.0%), followed by finances (26.4%), work or studies (18.3%), and relationships (4.3%). Missing data in this and the subsequent study was dealt with using pairwise deletion.On average, participants had worked on their nominated goal for 17.22 weeks  than to the past , Z = -5.68, p < 0.001, r = 0.26. In general, participants reported that they found it relatively easy to monitor their progress toward the nominated goal .Sign tests indicated that participants more frequently assessed their progress by comparing their current situation to a target state  = 2.48, p = 0.01, B = 0.09], if they thought about their goal progress in quantifiable terms , or if it pertained to social relationships . They were less likely to compare their current situation to the past if their goal was related to financial issues , or to work and/or study . Participants more frequently monitored their progress with reference to a target when they thought about their goal progress in quantifiable terms .Three linear regressions were conducted to examine which factors predicted: (a) how frequently participants compared their current state to the past, (b) how frequently they compared their current state to a target, and (c) how difficult they considered monitoring their progress to be. B = -0.31, SE = -0.02, t(480) = -7.24, p = 0.001, B = -0.31], and if they thought about their progress in quantifiable terms . Participants considered their goal progress to be more difficult to assess if the goal related to avoiding a negative outcome , and was related to work and/or study .As in Study 1, participants found it easier to monitor their goal progress if they felt confident of achieving their goal , or was related to finance , or work or study . However, they were more likely to monitor their progress with respect to a past state if they thought about their progress in quantifiable terms .B = 0.16, SE = 0.03, t(468) = 3.49, p = 0.001, B = 0.11] and/or when they thought about their goal progress in quantifiable terms .Participants more frequently monitored their progress with respect to a target when they had worked on their goal for a long period of time , if they thought about their goal progress in quantifiable terms , and if they had relatively high levels of self-efficacy . Participants found progress toward goals related to work and study  more difficult to monitor than goals in other domains.Participants felt that their progress was easier to assess if their goal was prevention focused [The findings of Study 3 support those of Studies 1 and 2 in showing that the more that participants thought about their goal progress in quantifiable terms, the more that they monitored their progress, and the easier that they felt monitoring to be. Also consistent with the previous studies, Study 3 showed that participants who were confident that they could achieve the goal also felt confident that they could assess their progress toward that goal. In keeping with Study 2, the results from Study 3 indicated that participants were less likely to assess their progress toward goals related to finance and to work and study with reference to the past, and they found monitoring their progress toward goals related to work and study to be more difficult to assess.Participants were less likely to monitor their progress with reference to the past if they had worked on their goal for a long, relative to a short, period of time. This finding is consistent with those of more likely to be evaluated with respect to the past). One explanation for the difference in findings may be the use of different measures in the two studies. For example, the question used to assess prevention focus in Study 2 asked participants to report the extent to which their goal was related to security and responsibility, whereas the questions used to assess prevention focus in Study 3 asked participants to report the extent to which working on the goal required them to engage in objectionable behavior. In addition, participants in Study 3 considered progress toward goals that were associated with a prevention focus to be easier to assess, but participants in Study 2 considered progress toward goals related to the avoidance of negative outcomes to be harder to assess, suggesting that a prevention focus may have reflected subtly different beliefs in the two studies.In contrast to Study 2, however, the results from Study 3 showed that progress toward prevention-focused goals was less likely to be evaluated with respect to the past , and they tended to have worked on their goal for longer (M = 25.27 weeks), than those in Study 2 (M = 17.22 weeks). Participants in Study 3 also tended to report a higher proportion of goals related to work and/or study (41.0%), than participants in Study 2 (18.3%). These differences may account for the differences in results found between the two studies.It is also worth noting that it may be difficult to make direct comparisons between the participants recruited for Studies 2 and 3, as there were some differences between the two samples. For instance, participants in Study 3 tended to be younger than those in Study 2 , and the frequency with which they make these comparisons. Study 1 interviewed participants to explore, in an open-ended, exploratory fashion, whether and how they monitored their progress toward goals that they considered to be important. The main findings were that: (a) progress on goals that pertained to security, responsibility, and/or the avoidance of negative outcomes was less likely to be assessed with respect to a target, (b) participants who had high self-efficacy felt that it was easier to monitor their progress, and (c) participants who framed their goal progress in quantifiable terms found it easier to assess their progress and were more likely to compare their current state to a target when assessing their progress.Studies 2 and 3 investigated similar relationships using a questionnaire design in which participants rated the nature of a nominated goal, along with whether and how they monitored their progress toward that goal. The findings of these studies supported Study 1 in showing that participants were more likely to assess their progress with respect to a target when they thought about their progress in quantifiable terms, and they also showed that participants were also more likely to monitor their goals with respect to the past for such goals. Also consistent with Study 1 was the finding that participants felt that their progress was easier to assess when progress was thought of in quantifiable terms, and when they felt confident that they would be able to attain the goal.People may more readily monitor their progress toward goals that they think about in quantifiable terms because people are more influenced by quantifiable information  when this information is readily apparent . Howeverless likely to compare their current state to a past state if it was prevention focused, as measured by questions adapted from the RFQ . The different relationships between prevention focus and the nature and extent of progress monitoring across the studies may relate to the fact that prevention focus was operationalized in a multidimensional manner, with at least two of the dimensions appearing to be independent of each other. Future research might seek to disentangle the effects of security, responsibility, and the avoidance of negative outcomes by independently manipulating them, in order to examine how each factor influences monitoring. Nevertheless, taken together, the evidence suggests that people are less likely to monitor their progress toward goals that pertain to the avoidance of negative outcomes than those that pertain to the attainment of positive outcomes. Further studies are, however, needed to determine why this is the case, as this relationship may be specific to certain characteristics of the avoidance goals focused on in the present research. Goals that involve maintaining, rather than changing, the current state  are probably less likely to engender changes in progress compared to goals where people are working toward changing their current state . As such, these types of goals may lead to less frequent monitoring not because they are more difficult to monitor, but because frequent updates on progress would be redundant.With regards to the effects of prevention focus on monitoring goal progress, Study 1 showed that participants were less likely to compare their current state to a desired target if their goal related to avoiding negative outcomes and/or to security and responsibility. In contrast, Study 2 did not demonstrate a relationship between prevention focus and use of a target to assess progress, but indicated that participants were more likely to compare their current state to a past state if the goal in question related to security and responsibility . In contrast, Study 3 revealed that participants were The second aim of the present research was to investigate the factors that are associated with how easy or difficult people find monitoring their goal progress to be. Across the studies, participants found it easier to monitor their progress toward goals that they felt more confident of attaining. However, self-efficacy was not associated with the frequency with which participants monitored their progress. This may suggest either that being confident about achieving the goal makes people feel that their progress is easier to assess , and/or that the ease of assessing progress increases peoples’ confidence in their ability to achieve the goal. For example, The present research employed a multi-method approach to identify factors that influence the nature, likelihood, and difficulty of progress monitoring. This was achieved by combining current theoretical perspectives . Our findings suggest that people find it easier to monitor their progress toward goals for which they feel confident of attaining, but harder to monitor their progress toward goals related to work and study. Finally, the findings suggest that people monitor their goal progress with respect to a desired target more frequently when they construe their goal progress in quantifiable terms, and that they find it easier to assess their progress toward such goals. Our hope is that these studies lay the groundwork for further theory-building and research on the antecedents of monitoring goal progress.This study was carried out in accordance with the recommendations of the British Psychological Society Ethical guidelines, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the ‘University of Sheffield’s Department of Psychology Ethics Committee.’BC designed and conducted all the studies in the paper. She also analyzed the data for all the studies, and wrote the article. TW proposed the research question for all studies, and was involved in the design of all the studies. He proofread the paper. YB was involved in the design of all the studies and proofread the paper. CS was involved in the data analysis of the first study, and proofread the paper.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.


Associations between frontal cortical thickness and the magnitude of d-amphetamine-induced [11C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD.Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [ However, recent studies suggest that, in healthy volunteers, gray matter density and volume are related to D2 receptor availability  in the midbrain, striatum, thalamus, amygdala, and diverse cortical areas  is thought to arise in part from alterations in catecholamine signaling  and 18 male healthy controls, all of whom took part in a previously reported study of DA function in treatment-naïve ADHD  than controls  . The longer interval for the ADHD group resulted from several outliers, and the median interval did not differ between groups . Before each scan, participants were asked to abstain from food, caffeine and smoking for 4 h and from alcohol for 24 h. A structural MRI was obtained on a separate day. The average interval between the PET and MR scans was 22.0 (SD = 21.9) for the ADHD participants and 21.8 (SD = 35.1) for the controls (p = 0.52). Toxicology screening occurred on the initial screening interview and prior to both PET scans.Participants first underwent an assessment to determine their eligibility to take part in the study based on the criteria described above. Eligible participants underwent two double-blind, randomized, and counterbalanced [68Ga transmission scan immediately prior to tracer injection. The emission scan started simultaneously with the injection of [11C]raclopride, as an i.v. bolus, and data were acquired for 60 min in 26 time frames of progressively longer duration. Vital signs were monitored and blood samples for plasma amphetamine collected just prior to capsule administration, at the time of tracer administration, mid-scan, and at the end of scan.Participants were scanned on a Siemens ECAT HR + PET scanner  with lead septa removed (63-slice coverage), with a maximum resolution 4.2-mm, full width at half maximum (FWHM) in the center of the field of view. Attenuation correction was performed using a 12-min TR = 22 ms, TE = 9.2 ms, flip angle = 30°, FOV = 256 mm, and matrix 256 × 256).High-resolution (1 mm) T1-weighted magnetic resonance images (MRI) were obtained on a 1.5-Tesla Siemens scanner, using gradient echo pulse sequence  , the dissociation constant of the radiotracer from the receptors (KD) and the free fraction of the non-specifically bound tracer in the brain (FND): BPND = FND*(BAvail/KD).As previously  defined on each individual's MRI. The ROIs were based on the functional organization of the striatum /BPND placebo × 100. Prior to analysis of associations of these values with CT, outliers in the distribution were winsorized  . Absolute native-space CT values (blurred to 20 mm) for each subject were entered into general linear models (GLM) predicting CT at each vertex from BPND and ΔBPND in the three striatal ROIs outlined above , Group membership (ADHD vs. Control), and the interaction of these terms, with total brain volume as a covariate:Statistical analyses were implemented using SurfStat, a statistical toolbox created in MATLAB by Dr. Keith Worsley  for non-isotropic images . The significance thresholds for these latter correlations were uncorrected, as RFT correction was not possible in these analyses.The effect of group membership on the relationship of CT with BPpost-hoc analyses were performed predicting vertex-wise CT and from BPND/ΔBPND in each group using the following GLM:To test the robustness of these correlations, confirmatory *BPND/ΔBPND interaction remained significant in the confirmatory group-wise analysis, it was considered a valid finding.This was done to identify associations that, despite contributing to an interaction, are weak and do not survive the RFT threshold on their own. This could occur (a) if an interaction is primarily driven by a strong association in one group and a weak opposite association in the other group ; (b) if an interaction is driven by two such weak associations, in which case the meaningfulness of the interaction is questionable. If a cluster showing a significant GroupND/ΔBPND, we also compared CT between ADHD and Control groups using both vertex-wise and a region of interest (ROI) analyses. The latter was performed because the significance threshold of the vertex-wise analysis (based on RFT) may be too conservative to detect significant differences in our relatively small sample. The vertex-wise analysis used the following GLM:Because possible group differences in CT between ADHD and Control groups, which have been reported previously  (Table ps < 0.0005). Because of this group difference and a significant correlation between BDI and ΔBPND in ADHD participants only (r = −0.68 p = 0.007), BDI was considered as a covariate, but it was not used in the final models since it did not improve the fit.The ADHD group did not differ significantly from Controls on any of the demographic variables. Estimated IQ was marginally higher in the control group (6) Table . Althougd-amphetamine-induced decrease in BPND in LST , but not in AST or SMST (ps > 0.1). In ADHD subjects, there were significant BPND decreases in all three ROIs . See Cherkasova et al. .BPt(31) = 2.04, p = 0.05], left insula , and left and right temporal lobes  but these trends did not meet family-wise correction for multiple comparison (p < 0.004).We examined whether cortical thickness differed between groups using vertex wise and ROI analyses. Vertex-wise analysis did not reveal any significant clusters. ROI analyses found greater CT in controls than ADHD participants in the right frontal lobe . Separate vertex-wise analyses in each group using RFT thresholding showed that the interaction was most prominently driven by a negative association between LST ΔBPND and CT in the control subjects  while in ADHD participants the association was positive . Separate vertex-wise analyses in each group showed that the interactions were primarily driven by positive associations between BPND and CT in the ADHD group. In these confirmatory analyses, clusters in the right (SMST) and left (AST) cerebellum , right anterior cingulate (SMST and AST), left posterior insula (SMST), and left occipital clusters (SMST and AST) and left posterior insula (SMST) remained significant in the ADHD group . Because of the size of these clusters and the strength of the associations, we report them in Table Group interacted with BP Figures , Table 4ND in the LST, the interaction was significant in three clusters located in the right posterior cingulate, left posterior cingulate and supramarginal gyrus . In these clusters BPND-values were inversely associated with CT in the healthy controls  but positively associated in ADHD . In the healthy controls, factor scores did not correlate with ADHD Index . Cortical thickness in the middle frontal gyrus cluster (that was associated with ΔBPND in controls) was not significantly correlated with ADHD index. In summary, regional cortical thickness associated with higher BPND correlated with severity of ADHD symptoms in ADHD subjects.As a final analysis, we examined whether cortical thickness in clusters that were associated with binding measures co-varied with symptom severity. Due to the number of clusters showing significant associations with baseline BPd-amphetamine-induced DA release in the LST were negatively related to CT. In treatment-naïve adults with ADHD, the opposite was observed. Second, in the ADHD adults, baseline striatal D2/3 receptor availability in sensorimotor and associative striatal sub-regions was strongly and positively associated with CT, most prominently in the anterior cingulate and insula. In comparison, in healthy controls, the relation between CT with D2/3 binding trended in the opposite direction. Finally, thinner cortex in the regions where cortical thickness was associated with baseline D2/3 availability was associated with more severe symptoms in the ADHD subjects.We report exploratory analyses of the relation between striatal DA function and cortical thickness. Two main findings were observed. First, in the healthy control group, individual differences in d-amphetamine challenge. ADHD subjects and controls showed divergent associations with cortical thickness for both.A negative association between striatal DA release and CT in healthy volunteers has been reported by us previously (Casey et al., ND in healthy individuals, consistent with the trends we report here. Positive associations in the ADHD subjects could then reflect an anomaly of cross-regulation of cortical and striatal D2/3 receptors.Little is known about relationships between striatal D2/3 receptor availability and cortical thickness in healthy controls. We did not detect significant associations in our previous studies, and the ones we detected here can only be considered trends. Woodward et al.  reportedThe most prominent associations of CT with D2/3 binding in ADHD subjects were seen in the anterior cingulate and insula, key components of the salience network (Seeley et al., Difficulties with sustained attention and engagement are hallmarks of ADHD. Not surprisingly, ADHD subjects have been repeatedly found to have aberrant task-related activity in key regions of the salience network Bush, , as wellpost-hoc nature, this finding could have implications for understanding emotional lability in ADHD. Emotional lability is increasingly recognized as an important contributor to functional outcomes (Shaw et al., d-amphetamine administration (Schrantee et al., Though the association of baseline D2 binding with anterior insula thickness should be interpreted with caution due to its Not all regions showing positive associations with D2/3 binding in the ADHD group belong to the salience network, and the meaning of associations in the cerebellum and cuneus is unclear. The cerebellum is thought to be closely linked with the salience network (Dosenbach et al., In conclusion, we found that stimulant-naïve ADHD adults did not show the negative association between amphetamine-induced changes in D2/3 receptor availability and prefrontal cortical thickness that we previously found in healthy controls (Casey et al., MC carried out the study, analyzed the data, and prepared the manuscript; NF recruited and tested four of the control and five of the ADHD subjects; KC recruited and tested four of the control subjects; KL contributed to data analysis; GO contributed to data analysis and manuscript preparation; LH and RJ ascertained the ADHD diagnosis for the ADHD subjects; GB was responsible for determination of plasma amphetamine concentrations; AE provided critical input on interpretation of cortical thickness relationships. AD participated in study design; JP participated in subject recruitment and testing; CB contributed to the study design, supervised data collection, and acted as the supervising physician during testing; ML conceived of the study, supervised data collection, and recruited and tested three control participants; ML and CB had full access to all of the data and take responsibility for the data integrity and accuracy of analyses. All authors discussed the results and commented on the manuscript.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.


Background: Tourette Syndrome (TS) is a neurodevelopmental disorder with childhood-onset, with a typical decline in tic severity, as well as an increasing ability to suppress tics in late childhood and adolescence. These processes develop in parallel with general improvement of self-regulatory abilities, and performance monitoring during this age-span. Hence, changes in performance monitoring over time might provide insight into the regulation of tics in children and adolescents with TS.Method: We measured reaction time, reaction time variability, accuracy, and event-related potentials (ERP) in 17 children with TS, including 10 children with comorbid Attention-Deficit/Hyperactivity Disorder (ADHD), 24 children with ADHD, and 29 typically developing children, using a modified Eriksen Flanker task in two testing sessions administered on average 4.5 years apart. We then compared task performance, as well as ERP components across groups, and over time using regression models.Results: Task performance improved in all groups with age, and behavioral differences between children with TS and controls diminished at second assessment, while differences between controls and children with ADHD largely persisted. In terms of ERP, the early P3 developed earlier in children with TS compared with controls at the first assessment, but trajectories converged with maturation. ERP component amplitudes correlated with worst-ever tic scores.Conclusions: Merging trajectories between children with TS and controls are consistent with the development of compensatory self-regulation mechanisms during early adolescence, probably facilitating tic suppression, in contrast to children with ADHD. Correlations between ERP amplitudes and tic scores also support this notion. Tourette Syndrome (TS) is a neurodevelopmental disorder with childhood onset, defined by the presence of multiple motor tics and at least one vocal tic over the period of 1 year or more  performance-monitoring pattern in terms of reaction times, variability of reaction times, and response accuracy similar to those of control children, whereas we expected better performance compared to children with ADHD. Further, we expected that children with TS would show (ii) ERP amplitudes similar to those of control children, whereas we expected that children with ADHD would show reduced ERP amplitudes in line with earlier findings. In addition, we explored associations between tic scores and ERP amplitudes under the assumption that tic control during adolescence is related to adaptation in control systems.N = 8, TS; N = 2), conduct disorder , phobia , anxiety disorder , transient tics , chronic motor tics , obsessive compulsive disorder , depression  and elimination disorder . All children were medication-free and had no prior treatment for ADHD at the first assessment. Participants taking stimulants at the second assessment  were asked to refrain from taking the medication in the 48 h prior to testing. Other types of medication  were taken as prescribed. Twenty-five children were girls and the groups did not differ for age and sex. Eleven children were left-handed  = 2.33, p = 0.03]. Lifetime worst-ever tic severity ranged from 14 to 23 (26.82 ± 8.13) at T1 and from 17 to 48 (31.00 ± 8.25) at T2, indicating a slight increase in the interval, consistent with the expected development  and the returning participants (N = 70). Age at first examination, gender ratio or handedness did not differ across groups. However, a difference of FSIQ scores for the control group (96.8 at first assessment vs. 107.7 at second assessment) was found. This was not present in the two other groups  included 39 children with ADHD, 25 children with Tourette syndrome and 35 control children aged 8–12. The study was approved by the Regional Committee for Medical Research Ethics, West-Norway and written, informed consent was obtained from the legal guardians/parents of all non-adult research participants. Inclusion criteria and results relating only to this cohort are described elsewhere  after verbal and written instruction and a training sequence. At the center of a PC screen, participants were presented a fixation dot. Trials began with the presentation of 6 horizontal flanker arrows appearing below the fixation. Participants were instructed to respond with their preferred hand as fast as possible and as accurate as possible with either a left or a right mouse button press following the direction of a central target arrow that appeared 100 ms after the flankers. The central target arrow pointed either into the same direction as the flanker arrows in compatible trials  or in the opposite direction in incompatible trials . The target and flanker-arrows remained on screen until a response was registered. Trials were terminated by a motor response and were followed by a fixed 800 ms interval before the onset of the next trial. Stimuli were presented in two blocks with 200 trials that were pseudo randomized separately for each participant. The overall probability of compatible and incompatible trials, as well as left and right responses was kept at 0.5, respectively. Performance feedback was given during the experiment when responses were erroneous or slower than the adaptive individual threshold value [mean response time plus 1.5 standard deviation (SD)].At both sessions electroencephalogram (EEG) was recorded during performance of a modified Eriksen flanker task implemented in the E-prime 2 experiment programming platform . Data were sampled at a 1,000 Hz-frequency with a 10 s time-constant, with Brain Amp MR plus X2 amplifiers . An elastic cap containing 34 Ag/AgCl electrodes placed at Fp1, Fp2, F7, F3, Fz, F4, F8, FT9, FC5, FC1, FC2, FC6, FT10, T7, C3, Cz, C4, T8, TP9, CP5, CP1, CP2, CP6, TP10, P7, P3, Pz, P4, P8, PO9, O1, O2, PO10, Iz was used. Channels were recorded against Fz with a ground on Fcz. Vertical eye-movements were recorded with a bipolar derivation between Fp1 and an additional electrode placed below the left eye, horizontal eye movement were recorded with a bipolar derivation between Fp1 and Fp2. Additionally, electrocardiographic activity was monitored by an electrode placed on the left chest. Impedances were kept below 10 kΩ.Continuous EEG data files were imported into EEGLAB written in Matlab , Reaction Time (RT), Reaction Time variability (sdRT), as well as the stimulus-locked ERPs P2, early P3, late P3, and response-locked ERN and Pe. We used a mixed-model analysis with repeated measures with an unstructured variance component matrix. The model included the within-subjects factor flanker outcome with three levels  for RTs, with two levels  for ACC, sdRT, and stimulus-locked ERP components, and with one level (error) for response-locked ERPs. In the longitudinal analysis, we included age at first and second assessment, as well as the three groups  as between-subject factor. In the cross-sectional analyses, age was included as a covariate. Additionally, RT mean from both assessments was included as a within-subject factor. A random effect variable, assumed normally distributed, accounted for individual responses of the participants. The model was adjusted for all two-way interactions between the variables diagnostic group, age, and condition. We transformed Accuracy to Arcsine to ensure a normal distribution in the outcome measure. We considered F = 744.06, p < 0.001] and showed group differences   = 153.13, p < 0.001]. An interaction of age by outcome approached significance . Directed post-hoc tests showed that, controls were faster than children with TS in compatible and incompatible responses at T1 . Developmental trajectories tended to converge for controls and children with TS during the second assessment where all reaction time differences were minimized . Children with ADHD and with TS did not differ in terms of reaction times in either of the assessments.Reaction times decreased with age , and differed across conditions , without interaction . Both diagnostic groups displayed a higher reaction time variability . Post-hoc tests revealed that controls showed significantly lower variability both in compatible and incompatible trials than children with TS and ADHD at the first assessment , whereas children with TS and with ADHD did not differ. At the second assessment, differences between ADHD and controls persisted , while differences between children with TS and controls only were present in incompatible trials (p < 0.05). When comparing both diagnostic groups at T2, reaction time variability was lower in children with TS compared with ADHD in incompatible trials (p < 0.05), and slightly lower in compatible trials (p = 0.06). This pointed at diverging trajectories over time in both incompatible (Δ TS vs. Δ ADHD p < 0.01) and compatible trials (Δ TS vs. Δ ADHD p < 0.05) between these two groups. In addition, differences between children with ADHD and controls increased over time in incompatible trials (Δ controls vs. Δ ADHD p < 0.01).Reaction time variability decreased with age , and differed across conditions . Groups showed differences in accuracy across both conditions , without a clear interaction . Post-hoc tests showed significant differences at the first assessment for incompatible trials between ADHD and controls (p < 0.01) and TS and controls (p < 0.05), but no group differences between TS and ADHD. Developmental trajectories converged at the second assessment for controls and children with TS and all differences in accuracy were minimized (n.s.). Differences between controls and ADHD persisted (p = 0.02), and children with TS were slightly more accurate than children with ADHD . In compatible trials, accuracy improved most in children with TS (Δ change p = 0.03), followed by controls (Δ change p = 0.05), while ADHD showed no relevant improvement. Performance for incompatible trials was more variable, and only children with TS showed a trend toward improved accuracy over time in incompatible trials (Δ change p = 0.08), while the other groups remained unchanged overall.Accuracy increased with age  without an apparent main effect or interaction of other terms . Direct comparison of longitudinal changes showed that ERN amplitudes increased from the first to the second assessment for all groups, however, average ERN amplitude appeared to become larger for controls and children with TS compared to children with ADHD, though without reaching significance .The ERN amplitude became larger with age , and simultaneously showed an inverse relation with response time changes . Amplitudes differed across groups  across both assessments with ADHD children showing lowest levels, and no interaction of age with group . Although children with TS appeared on average to show a slightly higher change over time than children with ADHD, no significant post-hoc group differences were found  = 17.94, p < 0.001]. Groups overall displayed similar P2 amplitudes , meaningful interactions were not seen, and developmental trajectories showed no relevant differences across groups.Younger participants had a higher P2 amplitude than older ones , also showing an inverse relation with response time . The overall developmental change did not differ between the groups in the full model , but post-hoc tests showed that children with TS had larger amplitudes in compatible trials than children with ADHD (p = 0.01) at the first assessment. Over time, compatible P3 increased for controls and children with ADHD . In incompatible trials, only controls increased in amplitude .The early P3 showed a significant increase over time , with larger amplitudes in incompatible trials and an inverse relation with response time . Late P3 amplitudes in compatible trials tended to decrease, whereas incompatible amplitudes marginally increased over time . Diagnostic groups did not differ in their developmental trajectories  , incompatible P2 , compatible early P3 , incompatible early P3 , incompatible late P3 . The ERN, however, correlated inversely with worst-ever total tic scores  for the second assessment, where this component was developed in contrast to the first assessment, where no apparent ERN was present in most participants. A positive correlation was also present with Pe from the second assessment . Worst-ever tic scores from the second assessment correlated positively with stimulus-locked amplitudes from the second assessment, compatible P2 , incompatible P2 , compatible early P3 , incompatible early P3 , incompatible late P3 . A positive correlation was present for the Pe from the second assessment  , and summarized overall test results here, along with directed F = 4.00, p = 0.01]. Post-hoc tests between TS only and TS+ADHD were not significant for all RTs at both assessments . Developmental trajectories did not differ between those two subgroups .For RT, the analysis showed group differences as previously . All post-hoc tests at both assessments between TS only and TS+ADHD were not significant . However, trajectories diverged between TS and TS+ADHD in compatible trials (Δ change p = 0.007) with lower reaction time variabilities for the TS only group over time, but not in incompatible trials (Δ change p = 0.08).Reaction time variability yielded a group main effect of similar strength . Post-hoc tests for both assessments as well as developmental trajectories did not differ between TS only and TS+ADHD .Groups showed differences in accuracy across both conditions , and shows a trend-significant post-hoc test at T1 , however trajectories merged between the groups and no differences were found at T2 .For the Pe, the analysis with four groups repeats a group difference , but post-hoc tests did not show differences between the two subgroups at T1 and T2 . However, incompatible late P3 amplitudes increased more over time in the TS only group compared to TS+ADHD, resulting in different trajectories for incompatible trials (Δ change p = 0.04), but not for compatible trials (Δ change p = 0.18).The overall developmental change of the late P3 revealed at trend-significant difference between the groups in the full model [age × group: t-tests and effect size estimators.While it is noteworthy that some of the measures here showed differences between TS subgroups at T1 or T2, or in terms of change over time, the majority of the data available to us showed no sign of more widespread differences when using two-sample The present examination of attention, cognitive control, and performance monitoring from childhood to adolescence revealed several differences of the developmental trajectories between children with TS, and healthy controls, and in contrast to children with ADHD. Task performance in terms of reaction times, reaction time variability, and accuracy improved in all groups with age, but behavioral differences between children with TS and controls diminished at the second assessment, whereas differences between controls and children with ADHD largely persisted. In terms of ERP, the early P3 developed earlier in children with TS compared with controls and trajectories converged with maturation. Worst-ever total tic scores correlated positively with stimulus-locked ERP from the first and inversely with response-locked ERP from the second assessment in children with TS.The developmental effects on performance for the overall group with increased accuracy, faster reaction times, and decreased reaction time variability are consistent with the literature (Posner and Rothbart, In contradistinction, despite general improvement in performance over time in the ADHD group, most of the ADHD-related performance differences with respect to behavioral performance persisted through development in direct comparison with the controls. The significant group-effect for reaction time variability and error rate in children with ADHD is in line with findings that increased variability and error rate are particularly robust markers of ADHD (for review, see Mullane et al., Maturation had a strong effect on the ERP components in the overall group with younger children showing smaller amplitudes in ERN, PE, early P3, and incompatible late P3 while P2 and compatible late P3 amplitudes decreased with older age. The age effects on the error-related components for the overall group with increasing amplitudes of ERN through adolescence are consistent with prior studies (Davies et al., Larger amplitudes in early P3 in children with TS compared with controls were seen in the first assessment (Eichele et al., For the remaining stimulus-locked ERP amplitudes, we observed marginal changes over time. Across trial conditions, ADHD showed smallest amplitudes in the late P3, while TS and controls showed larger amplitudes. There was no appreciable change of compatible amplitudes for the ADHD group, while the TS and control groups showed subtle amplitude reduction over time. On the other hand, the developmental trajectories of the incompatible late P3 increased slightly, and merged in adolescence for TS and controls, but not for the ADHD group. This suggests normal maturation of attention functions and non-significant attenuation in children with TS. For the P2 we expected an amplitude reduction over time based on normative studies (Allison et al., The moderate to strong correlations between several ERP amplitudes and the worst-ever tic scores are striking. Positive correlations with stimulus-locked ERP from the first and inversely with response-locked ERP from the second assessment may suggest that the associations provide an indicator for a higher symptom load earlier in life leading to changes in stimulus and motor processing, resulting in a an inverse correlation with error-related amplitudes at a later stage. It has been proposed that children with TS gain tic control through compensatory mechanisms that involve alteration of prefrontal control over motor output, experimental support comes specifically from supplementary motor area (Jackson et al., t-tests between these subsamples in the dependent measures and did not find any significant differences between these subsamples. To complement the t-statistics, we also estimated Hedges g for the total TS sample vs. ADHD, and for the TS-ADHD subgroup vs. ADHD from all relevant dependent measures, and found no robust differences in terms of average effect size. This may justify the inclusion of children with TS only and those with additional ADHD in the same group. The relative lack of negative impact of comorbid ADHD on TS in our sample seems at variance with previous work reporting impaired ERPs (Shephard et al., t-tests of the baseline characteristics between participants lost to follow-up and remaining participants, both for the overall group as well as for the diagnostic groups separately and found no significant differences. We also reviewed the reasons for dropout based on debriefing information for the TS group, only one child did not further participate due to reduction of symptoms, for the remaining seven participants that did not return, other or no reasons were given.Among the limitations of our study, the relatively small sample size should be mentioned which also required disregarding comorbidities, use of medication, as well as the utilization and efficacy of behavioral treatment options. The latter information was unfortunately not available within the current study setup. Ideally, the impact of comorbid conditions and medication should be assessed separately, and in more detail, however, we performed explorative Taken together, the present examination of cognitive processes from childhood to adolescence helps us to further broaden our knowledge of electrophysiological correlates in children with TS over time. During development, electrophysiological and behavioral differences between controls and children with TS decreased and trajectories converged with control children. This may point at compensatory adaptive processes that mitigate symptoms load in children with TS over time. This is in contradistinction to residual deficits in adolescents with ADHD which continued to show reduced performance at both time points. However, some reduction of deficits in absolute terms was also apparent for other measures upon visual inspection, and may have missed significance due to lower statistical power with our overall small sample size.The developmental changes seen in children with TS support theoretical accounts of the development of cognitive control stating that the ongoing maturation of the prefrontal circuitries, including the ACC, plays a major role in the development of cognitive control (Posner and Rothbart, The here presented indications of early compensatory effects may contribute to clinical awareness concerning underlying neurobiology of plastic processes and compensatory effects already in earlier age that may indicate that children with TS could benefit from habit reversal training already before the recommended age. Further, enhancements in adaptive processes through specific interventions may in the future decrease some of the impairments associated with TS, and thus improve quality of life in this patient group.Conception and design: HE, TE, LS, KH, and KP. Acquisition of data: HE, TE, LM, SA, and LS. Analysis and interpretation, writing of article: HE, TE, and KP. Critical review of article and agreement to be accountable for all aspects of the work: HE, TE, LM, SA, KH, LS, and KP.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. The reviewer MB and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.