Healthcare workers are considered key stakeholders in efforts to address vaccine hesitancy. Midwives’ influence in advising expectant parents on early-childhood vaccinations is unquestioned, yet they remain an understudied group. The literature on midwives’ attitudes towards vaccinations is also inconclusive. We therefore conducted an explorative qualitative study on midwives’ vaccine-hesitant attitudes towards MMR (measles-mumps-rubella) vaccinations in Austria.We conducted 12 in-depth interviews on their knowledge, concerns, and beliefs with midwives who self-identified as hesitant or resistant towards early-childhood MMR vaccinations. We analyzed the data using a grounded theory approach to distill common themes and meanings.Healthcare workers’ stewardship to address vaccine hesitancy is commonly framed in terms of the “information deficit model”: disseminate the right information and remedy publics’ information deficits. Our findings suggest that this approach is too simplistic: Midwives’ professional self-understanding, their notions of “good care” and “good parenthood” inflect how they engage with vaccine information and how they address it to their clients. Midwives’ model of care prioritized good counseling rather than sharing scientific information in a “right the wrong”-manner. They saw themselves as critical consumers of that information and as promoting “empowered patients” who were free, and affluent enough, to make their own choices about vaccinations. In so doing, they also often promoted traditional notions of motherhood.Research shows that, for parents, vaccine decision-making builds on trust and dialogue with healthcare professionals and is more than a technical issue. In order to foster these interactions, understanding healthcare professionals’ means of engaging with information is key to understanding how they engage with their constituents. Healthcare workers are more than neutral resources; their daily praxis influenced by their professional standing in the healthcare system. Similarly, healthcare professionals’ views on vaccinations cannot be remedied with more information either. Building better and more diverse curricula for different groups of healthcare workers must attend to their respective roles, ethics of care, and professional beliefs. Taken together, better models for addressing vaccine hesitancy can only be developed by espousing a multi-faceted view of decision-making processes and interactions of healthcare workers with constituents. In 2019, the World Health Organization identified vaccine hesitancy (VH) as one of the “10 Threats to Global Health” in light of increasing reluctance or refusal to vaccinate and a surge in cases of vaccine-preventable diseases . Within Research shows that healthcare workers (HCWs) play a key role in promoting vaccines –13. TheyThe issue of early-childhood MMR vaccinations is exemplary in Austria not only given rising incidence. Before the recommended age for MMR vaccines dropped to 10–12 months in the late 1990s, vaccinations were performed for school-aged children during school hours among a group of peers. The shift redistributed to (new) parents the responsibility to decide whether or not, and when, to vaccinate their children.Generally claimed to harbor more hesitant attitudes towards vaccinations , midwivekind of midwife expectant parents can afford.Austria is classically characterized a conservative welfare state with a universal, state-financed social health insurance (SHI) system and a “familistic orientation of its public policies” . As suchThough more complex in its details, the Austrian healthcare system can more simply be divided in a statutory public sector and a supplementary private sector. Midwives on duty in hospital maternity wards will attend births but generally do not maintain close and consistent contact with parents before or after birth. The majority of midwives, as represented in our study, work as independent midwives who accompany mothers during pregnancy, childbirth, and in the postnatal period. Their services have to be independently organized and paid out of pocket by expectant parents. Costs will vary depending on services but may lie upwards from €1500 or €2500 for home/extramural births.Within this institutional pretext of the Austrian healthcare system, our article closely explores the specific concerns, beliefs, and attitudes of midwives who identify as hesitant or resistant towards early-childhood MMR vaccinations in their relation to expectant parents.Social-science research has shown that publics’ hesitant attitudes towards vaccines are not so much the result of information deficits, nor reducible to a single choice, but rather embedded in a web of cultural attitudes, ideas, and health-related decision-making –37. In sremedy midwives’ information deficits regarding vaccines, rather than understanding their particular role in vaccination practices.In this vein, our article discusses results from a case study on Austrian midwives’ rejection or hesitancy towards MMR vaccinations. In their exemplary review of the literature, Attwell and colleagues  identifiIn the following, we first detail our methodology. We then present our findings, focusing on three particular themes that emerged in our inductive analysis: midwives’ role and self-understandings; the notion of care that shapes their practices and epistemic stances; and the links they draw between lifestyle choices and vaccination attitudes. We conclude by situating these findings in the current literature and formulate a set of recommendations as to moving beyond the current information deficit thinking.This research was conducted at the Medical University of Vienna as part of multiple qualitative studies supervised by one of the authors (RK) that investigated vaccine-hesitant attitudes of parents and HCWs towards childhood MMR vaccinations in Austria .Qualitative studies are apt tools to explore topics hitherto under-researched and interviews allow exploration of reasons, meanings, and dogmas in what is said. The underlying constructivist paradigm holds that “the ‘reality’ we perceive is constructed by our social, cultural, historical and individual contexts” , so thatWe recruited midwives who self-identified as hesitant or resistant towards MMR vaccinations and/or vaccinations in general, meaning that they claimed for themselves the label “vaccine skeptical” in the German vernacular by responding positively to our recruitment efforts.Initial recruitment in/around Vienna using opportunity sampling via vaccine-hesitant physicians, on Facebook message boards, and at midwife centers or the National Committee of Midwives proved unsuccessful. Midwives often declined participation claiming that the topic was too contentious, and they were not knowledgeable enough or did not share their opinions with parents. Telephone calls (50), with contacts sourced from the public directory for midwives or through online searches only yielded three initial interviews. We then proceeded by snowball sampling and word-of-mouth from participants provided a majority of interviews. After eight interviews, JG actively sought out midwives to ensure a broader distribution of significant characteristics in the sample such as age, vaccination attitudes, and employment status (targeted sampling). Participants were recruited until no new relevant knowledge was obtained (data saturation).Interviewees were between 28 and 58 years of age, all identified as women, and variably worked as independent, attending, or SHI-contracted midwives. A majority were working  as independent midwives and a minority had SHI contracts. This mirrored the overall employment distribution of the around 440 midwives employed in Vienna at that time , 50 Tab. The 12 We conducted the interviews as semi-structured, narrative one-on-one interviews between May and November 2017, either at home (5) or at midwives’ place of work (7). Interviews were 30–60 min long, conducted in German, audio-recorded, transcribed verbatim (JG), and subsequently translated for publication (LL). An interview guideline assured comparability between interviews and provided overall structure. Questions were first developed deductively from existing literature, but continually refined inductively in line with Grounded Theory principles to integrate initial findings. They covered three general areas: (1) professional position, training, and continuing education; (2) attitudes towards measles disease and MMR vaccination, information, consultation, and public perception in Austria; (3) personal experiences with vaccination practices. Interviews remained open-ended to allow interviewees to introduce their own topics, expound on their beliefs, and use their own words.LL analyzed full transcripts using Atlas.ti  and emplThe study was approved by the ethics review board of the Medical University of Vienna. Interviewees were informed of the course and aims of the study beforehand, provided written and verbal informed consent on a pre-approved consent form, and could decline answering questions or discontinue the interview at any point, though none did. To protect midwives’ professional position they were guaranteed pseudonymity; all names used are pseudonyms and additional identifying information was redacted.“already a little too far distanced from measles vaccinations. It’s a topic to discuss with the pediatrician, very specifically. Because I think that is the person who kind of carries it all” . Many of the midwives therefore talked about sending their clients to discuss vaccinations with their physicians.Interviewees considered themselves in a marginal role within the maternity care system in Austria with regard to vaccinations. They often expressed this view by pitting their professional identities against those of pediatricians and by articulating distinct ideas about their respective jurisdictions in vaccine decision-making. They put vaccinations within physicians’ purview as progenitors of Western biomedicine, in charge of performing and speaking authoritatively on vaccinations. Zoe, for instance, admitted that she was “handing over”  the issue of vaccination decision-making to a pediatrician with whom she closely cooperated. Yet, for Zoe and many of the others, such professional distance to vaccinations engendered tension. They talked about having to actively stop themselves or blocking parents from asking further questions. Hannah noted, “Almost every third [woman] or every third couple asks me [about vaccinations] during postnatal care. And I don’t engage in that. I’m not the person to talk to about that” .Many of our interview partners described cooperation during maternity care despite potential professional divides. Some, if they had the chance, recommended pediatricians they trusted or “matched” pediatricians to the vaccination attitudes of parents as they came to know them. Rita talked about “hot-button issue.” In their experience, vaccination decisions did not appear clear-cut but an urgent topic of discussion and involved lengthy deliberations for their clients before birth. Yet, in their view, lack of time and preparation posed significant hindrances in meeting these needs. An ideal process of awareness-raising about vaccinations would prepare expectant parents, especially mothers-to-be, well in advance. By this measure, many of the midwives found the system — for lack of patience or time — ill-equipped to address their clients’ questions and doubts. Our interviewees often saw a worrying disconnect between what they thought was the best care for expectant parents and what was provided by pediatricians. Stephanie voiced a common concern regarding interactions between parents/mothers and doctors, “It’s a problem. Some mothers, they can’t find a pediatrician anymore who can respect a mother who says, ‘I don’t want to vaccinate my child” . Midwives recounted stories of pediatricians refusing to see anyone who questioned vaccinations. Ida mused that pediatricians “only hear, ‘I don’t want to vaccinate’ and— alarm, alarm! Because it’s already the 15th mother that day, who doesn’t want to vaccinate, and of course he [sic] might get impatient then” . Indeed, some of the midwives doubted the capacity of overburdened state-funded healthcare to meet the need of comprehensive information and deliberation.Overall, the midwives described vaccinations as a “a very narrow area of medicine” . Though, within that area, they understood their practices as moored in professional ethics and a notion of “good care” distinct from physicians.The midwives did not see themselves as usurping physicians’ jurisdiction in propagating information about vaccinations. Hannah noted that midwives inhabited only good midwifery meant camaraderie with other midwives, sharing knowledge amongst one another, providing women in their care with thorough attention, and acting as knowledgeable counselors. In this, the midwives pitted themselves against an engagement with clients that, in their view, issued instructions and gave orders — a model of care they associated with (bio)medicine. Consequently, it was important to the midwives that they kept their distance from clients’ vaccine-decisions because they understood themselves neither as authorities nor “missionaries” of any single position. They appealed to taking a “neutral” stance, leaving final decisions to their clients.For those midwives we interviewed, “Physicians don’t give good explanations around vaccinations. They don’t know a lot of things, I feel like. Many don’t really have a plan and follow what the Ministry of Health or the National Board of Vaccination recommend” .Many felt that it was their professional responsibility to read up on vaccinations and recommend further information to clients. Indeed, all of the midwives interviewed detailed the many sources they accessed for information: books, message boards, the internet, and personal contacts among midwives or physicians. Asked how they had learned about vaccinations during their training, our interviewees recounted that it had hardly been part of their curriculum except for the national immunization plan. Patricia directly connected the plan to state governance, for whom she saw physicians acting as messengers, “regulation”  from state authorities. They saw physicians as acting in a “one-sided,” pro-vaccination manner. In the name of “neutral explanations,” the midwives instead endorsed alternatives to that mainstream. For them, being hesitant to accept vaccinations was about fighting the status-quo from what they considered a position of opposition and promoting individual choice and agency. “It’s like in politics,” summarized Rita. “There is one party that governs for many years, decades if you like. And there’s an opposition. And that opposition is really important so that the governing party can’t just do what it wants” . In so doing, she also hinted at a sense of marginalization that midwives experienced in this particular context.Patricia expressed a view common to some of our interview partners: that vaccinations represented a “important for us in maternal care, in child-rearing, in childcare. So that the system gets broken up a bit, gets a bit more flexible” . Astrid similarly demanded flexibility. She talked at length about how she had “become skeptical over time” — both as a professional and regarding vaccinations — while becoming more involved with groups of midwives that “dared to experiment”  in the 70s. Drawing on this history of opposition against the status-quo and midwifery ethics of care, both of them demonstrated hesitancy to follow immunization plans by the letter or seeing physicians do so. Like them, many of the midwives we interviewed considered their vaccine-hesitant attitudes their own personal beliefs. At the same time, the midwives often split the difference between their hesitancy about vaccines and their professional roles by adopting an arguably “neutral” stance. Coupled with possibly inadequate critical training, this saw many of the midwives treating variable sources of information as equal in their counseling of clients.An experienced midwife, Rita also saw alternative approaches as having been “If you ask a ‘home-birth midwife,’ she is probably going to have more women who don’t vaccinate at all” . For Barbara, this stereotype had real-life consequences for the treatment of women. She felt that pediatricians were particularly skeptical towards women who had home-births, so much so that “when the pediatrician sees that they had a home-birth, he [sic] will say, ‘Ah, so you won’t want to vaccinate either.’ More or less, they put them in a box, ‘Those who have-home births, they don’t like vaccinations.’” Barbara could not agree with that sentiment; rejection of vaccinations was not at the heart of it. What mattered was information and acting on it, “Our parents just want to get informed. Maybe more so than others” .Maternity care in Austria is primarily hospital-based and overseen by physicians . In ligh“our parents,” juxtaposed with generalized “others,” pointed to a particular type of client more common for the midwives we interviewed. The midwives implicitly or openly referred to this type of client as an “empowered patient.” This patient did their research, asked questions, and was independent in their choices. Our interviewees generally considered it essential to encourage parents to “remain critical” of taken-for-granted interventions like vaccinations. Adding a gendered valence to this need for agency, interviewees often referred solely to “mothers” and “women” in this context, even if they otherwise talked about “couples” and “parents.” Here, they considered it a professional responsibility to “activate women to inform themselves” .The proprietary defend themselves, so that the opposite side knows, ‘Okay, they are well informed and they can’t be palmed off with some kind of instruction’” . The empowered patient, then, was privileged and had the means to make such investments. Indeed, many of the independent midwives provided care for affluent clients. Stephanie explained that “it’s not the average mother that I work with who can afford a midwife and who values a personal midwife. They have to pay for that. I’m not an SHI-contracted midwife who really works with a variety of people” . In this context, many of the midwives identified a larger commitment in choosing a “no-vaxx” lifestyle or one of delayed vaccination.Such activations, though, came with demands. Some of the midwives we interviewed, like Jessica, considered it a parent’s duty to get informed. They had to have competence, Lisa noted, to ““not just meaningless,” but as Lea noted, “Midwives generally don’t go at it with a pathological perspective on things but in principle assume that the individual is in a state of health” . Measles disease was framed as a “childhood disease” and thus a “natural” immunological life-event. Zoe thought it “simply important that you somehow go through [measles]”  during childhood, and Astrid was certain that “childhood diseases aren’t anything dramatic. Because childhood diseases are childhood diseases. We all went through them” .For most of our interviewees, vaccinations presented a generalized intervention that lacked a person-centered perspective focused on child and family. It also presented an artificial manner to induce life-long immunity that would come about naturally through falling ill and recovering. Many of our interviewees considered diseases “ideal” diet, and living in a “sheltered” familial environment. Measles could be managed without vaccinations but that required guidance from trusted HCWs and demanded competence from parents, as well as emotional awareness. Lea cautioned that “sitting there and watching” your child, sick with measles, was “a path that you need to be able to endure” . Parents also needed time and the means to care for a sick child. Sick children were best kept at home for as long as they needed to. Ida was blunt about parents who did not enjoy the necessary socio-economic opportunities in that “they really just have to vaccinate their children, simply because they don’t have the time to care for their really sick children” . Vaccinations became important, therefore, for children who required “out-of-home childcare” in nurseries or kindergartens as they might not be “as stable within or not as protected” . In these considerations, affluence and/or traditional familial structures were implied: the economic means for parents to stay home for prolonged periods of time and a family model with one stay-at-home parent — more often than not, in the context of Austria’s maternity leave provisions, this meant mothers.By the same token, interviewees deployed strong beliefs in the influence of environment on childhood immunity, especially familial units. A complex interplay of strengths and weaknesses had to be considered and actively provided for. Getting sick and being able to recover was mediated by multiple factors like whether or not children were breastfed, receiving an more information to them will prove insufficient.Our article provides an in-depth perspective on midwives’ concerns, attitudes, and beliefs regarding early-childhood MMR vaccinations. We especially highlight the shortcomings of the “information deficit model” on two fronts: First, by regarding HCWs as neutral brokers or “multipliers” of information, the model’s attendant logic affords little attention to the process of multiplication itself. Professional ethics around “good care,” the self-understanding of HCWs, and their role within the healthcare system inflect how they address their constituents and how they engage with information. Secondly, training for HCWs needs to take these aspects into account; simply providing The midwives we interviewed situated themselves within the larger Austrian maternity care system by engaging in “boundary work”  against The midwives prioritized “naturalness,” the premise of physiological health, and the mother-and-child dyad. Within this frame, the midwives did not consider the science of vaccinations “theirs,” placing explanations to parents in the purview of pediatricians. Rather than sharing information in a “right the wrong”-manner, good midwifery care for our interviewees meant recommending further information, sharing personal opinion, or offering advice when prompted. Pointing parents to immunization guidelines, which they often assumed to be their designated role in the system, appeared insufficient to many and incompatible with being “good counselors.” Sobo, who has re-theorized vaccine refusal as an affiliative practice, notes that the act of refusal is “neither the primary feature nor the first step in refusing.” Rather, it is preceded by a selection process and a different understanding of the world and how its pieces hang together . Many ofAt the heart of this was midwives’ desire to remain and retain their clients’ capacities as “empowered patients,” just as they often saw themselves as empowered by virtue of their professional training. Only such could their clients evolve expertise and make independent informed decisions for their children in a nexus of neoliberal consumer culture, the democratization of expertise, and attendant demands on “good” parenthood . For ourYet, such choices remain unavailable to parents and women with the least resources. In that sense, midwives in Austria have become shorthand for a particular kind of middle-class parenting, linking affluence and VH , 65. As The list of potential measures to address VH is long , 69. ResIn their paper on parents’ logics of vaccine hesitancy and refusal, Ward et al. respond to parents’ distrust of doctors and pharmaceutical companies — or, more generally, the larger system of Western biomedical authority — by posing a central question for public health going forward: “how do we get the message there in an appropriate manner and what message will be accepted?”  Our studVaccine decision-making is more than a technical issue for parents, research shows. The evidence of science and medicine plays only a partial role. Similarly, the language of risks and statistics do not easily connect to the wellbeing of a single child and trust is built through dialogue –73. Bett


No statistical significant effect of both groups  for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, sleep WASO and total number of wake bouts was observed. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. ATO induced the rhythmicity of Clock in the ADHD group. This effect, however, was not observed in HDF cultures of healthy controls. Bmal1 and Per2 expression showed a significant ZT × group interaction via mixed ANOVA. Strong positive correlations for chronotype and circadian genes were observed for Bmal1, Cry1 and Per3 among the study participants. Statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as healthy participants with morning preferences. The results of the present study illustrate that ATO impacts on circadian function, particularly on Clock, Bmal1 and Per2 gene expression.Atomoxetine (ATO) is a second line medication for attention-deficit hyperactivity disorder (ADHD). We proposed that part of the therapeutic profile of ATO may be through circadian rhythm modulation. Thus, the aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after ATO exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with a diagnosis of ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After  Circadian rhythmicity is a fundamental feature of mammalian physiology that has developed under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the inner clock to anticipate and respond to several environmental stimuli. In modern technological societies, circadian entrainment is subjected to alterations from artificial lighting as well as lifestyle changes. These alterations lead to the increased development of disorders, e.g. attention-deficit hyperactivity disorder (ADHD), depression, obesity, as well as diabetes (Gerhart-Hines and Lazar Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders. The disease persists into adulthood in 40% of children with ADHD . Individuals with a diagnosis of ADHD often exhibit disturbances in the circadian day-night rhythm  have detected associations between chronotype and genotype Gaspar. Lane etN-methyl-d-aspartate receptor antagonist in rat cortical neurons  is a second line pharmacological treatment for ADHD, besides methylphenidate, which sometimes is associated with adverse reactions and intolerance. ATO is a selective noradrenaline reuptake (NET) inhibitor. It increases norepinephrine and dopamine extracellular levels in the prefrontal cortex of rats  derived from ADHD and healthy individuals. Patient-derived HDF cultures have the advantage of being independent to light exposure and express the majority of the same receptors and pathways as neurons, including catecholamine pathways. HDFs cultures are easily established from skin biopsies and provide an advantageous model to study circadian rhythmicity and the influence of drugs on circadian gene expression  to evaluate the circadian preference, behavioral circadian as well as sleep parameters in healthy participants and patients with a diagnosis of ADHD (2) and to examine the molecular levels of clock genes after exposure of primary human-derived dermal fibroblast cultures to ATO.in vitro.Based on the assumption of the effectiveness of ATO for the treatment of ADHD, its influence on the expression of circadian genes is hypothesized. Therefore, in this study, the influence of ATO on circadian rhythmicity is investigated Ethical approval for the conduct of the study, including obtaining human dermal biopsy samples, was given by the ethical review committee of Rostock University (Registration-number: A2013-159) and written consent was obtained from each study participant. The study was conducted according to the ethical guidelines of the Declaration of Helsinki.In total, 12 volunteers without a neuropsychiatric diagnosis  and 12 volunteers with attention-deficit hyperactivity disorder (ADHD) participating in the study were recruited via the Department of Psychiatry and Psychotherapy, University Medical Centre Rostock. All ADHD subjects meeting DSM-IV and ICD-10 criteria diagnosed by experienced psychiatrists in advance. The healthy control group was recruited of acquaintances of people involved in the study.Human dermal fibroblasts (HDF) were obtained from skin biopsies from dorsal forearm from ADHD patients and healthy control volunteers. Only adult individuals, able to give informed consent, were included. Healthy controls without a history of childhood and adult ADHD were matched for sex and age. Patients with more severe psychiatric symptoms were excluded, as were shift workers. Screening for ADHD symptoms was done by assessment of symptoms according to DSM-IV and ICD-10 criteria. Additionally, the following psychometric tests were used to confirm ADHD diagnosis: Wender Utah Rating Scale (WURS-k), SKIDI and II , DIVA 2.0 (Structured diagnostic interview), CAARS  and PSQI . The IQ of the healthy control group and volunteers with ADHD diagnosis was measured using the Multiple Choice Word Test (MWT). The chronotype of the participants was determined by the Morning-Eveningness-Questionnaire, German Version (D-MEQ). No special cognitive testing was implemented in the study.Comorbidities were observed: 16.7% of participants with ADHD diagnosis has additionally adipositas, 8.3% has additionally addiction disorder, and 25% has additionally affective disorder. The remaining participants with ADHD diagnosis have no comorbidities.The four manuscripts of this special issue dealing with circadian rhythmicity describe unique research questions . Actigraphs were worn on the non-dominant wrist for a period of at least 7 consecutive days. The recording interval of the device was set at 60-s epochs. Data occurring before the first and after the final midnight of each record were excluded, ensuring at least 6 complete days for each participant, with a complete weekend included in each record.2) in Dulbecco’s Modified Eagle Medium DMEM /1 mg/ml Liberase TM  containing 100 units/ml penicillin, 100 µg/ml streptomycin  and 10% fetal bovine serum FBS .Human dermal fibroblasts (HDF) were isolated and cultured as described previously  Reference Standard, Merck, Germany) in DMEM with 5% FBS. Following 24 h, cell viability was measured using the Trypan Blue Exclusion Test Strober .N-lauryl sarcosine, 25 mM tri-sodium citrate, 0.1 M betamercaptoethanol) and stored at − 80 °C. mRNA was isolated and purified with RNeasy Plus Mini Kit  as well as subjected to reverse transcription using the Superscript III First-Strand Synthesis System . Gene expression of Clock, Bmal1, Cry1, Per1, Per2, and Per3 as well as housekeeping genes, Rpl13A, Rpl19A, GAPDH, was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with CFX Connect™ Real-Time PCR Detection System . All primers were purchased from Eurofins . The oligonucleotide sequences are presented in Table Rpl13A, Rpl19A, GAPDH from the same sample was used  Reference Standard, Merck, Germany) in DMEM with 5% FBS for 24 h. Cultures without ATO were used as a negative control. The following day, the cells were synchronized with 100 nM dexamethasone  for 30 min. Samples were harvested every fourth hour after synchronization for a period of 28 h in GTC lysis buffer . The data were set to an assumed period of 24-h and with α set at 0.05. The center-of-gravity of each best-fitting waveform in CircWave was used as the circadian acrophase, and the associated estimation error was used as the SD. Inferential statistics were carried out in SPSS (IBM Corporation). Actigraphic data were analyzed via MANCOVAs, with age, sex and in some cases, ADHD symptom severity included in the model as covariates.To determine the best-fitting linear harmonic regression, circadian gene expression data were tested for significant circadian rhythmicity, using CircWave v.1.4 software  with 3 measures . Although research in this field is generally scarce, we assumed that the influence of ATO on the circadian gene expression will have an effect size d’ = 0.5, returning a required total sample size of 21. Taking into consideration, an expected drop-out rate, n = 12 participants were allocated to each group.qRT-PCR clock gene data were analyzed via ANOVA and mixed between-within ANOVAs. One-way ANOVA was used to assess differences of clock gene expression levels among chronotype groups. Associations between clock gene expression and chronotype obtained from healthy controls and ADHD participants were studied by Spearman’s rank order correlation. For all inferential tests, Data were analyzed via time series statistics adequately powered by 12 samples each, which in this statistical model is mathematically sufficient and thus representative  and volunteers with attention-deficit hyperactivity disorder (ADHD) . All participants completed the Multiple-Choice Word Test , Morningness-Eveningness-Questionnaire, German Version  and Wender Utah Rating Scale, German Short Version . The demographic data are presented in Table Human dermal fibroblasts (HDFs) were obtained via skin biopsy from healthy controls (HC) . Bonferroni post hoc correction demonstrated no significant difference for mid-sleep on weekend days (p = 0.774), mid-sleep on weekdays (p = 0.382), social jetlag (p = 0.553), sleep efficiency (p = 0.975), WASO  and total number of wake bouts (p = 0.659).Measures from the non-parametric circadian rhythm analysis were analyzed between both groups, healthy controls and ADHD participants, in a MANCOVA. Age and sex were chosen as co-variates. No statistically significant effect of group was observed . A significant difference for mid-sleep on weekend days (p = 0.008), mid-sleep on weekdays (p = 0.001), but not for social jetlag (p = 0.928), sleep efficiency (p = 0.715), WASO  and total number of wake bouts (p = 0.570) was observed. The measurements for two ADHD volunteers were not completed.Measures from the non-parametric circadian rhythm analysis were analyzed across the two groups, healthy controls and ADHD participants, in a MANCOVA with chronotype as co-variate. No statistically significant effect of group was observed  after ATO incubation was compared with HDFs without ATO. The viability of cells treated with ATO  was marginally decreased compared to control cells without ATO .The expression profiles of circadian genes after incubation with 0.20 µM and 0.58 µM ATO concentrations were examined in primary fibroblasts cultured from skin biopsies collected from ADHD and healthy participants and synchronized with dexamethasone. Cultures without ATO were used as a negative control.Circwave analysis revealed a significant rhythmicity of Clock gene  in the cultures collected from the ADHD participants incubated with 0.58 µM ATO. This effect was not observed in other HDF cultures.p < 0.01). Bmal1 expression showed a significant zeitgeber time ZT × group interaction via mixed ANOVA , as well as Per2 expression . No ZT × group interaction via mixed ANOVA was observed for Clock , Cry1 , Per1  and Per3  expression.Mixed between-within ANOVA analysis of circadian gene data with group as between-subject factor and time as within-subject factor showed significant main effects for time for all circadian genes  and ADHD (p = 0.019). The same effects were observed in HDFs from volunteers with a diagnosis of ADHD with 0.58 µM (p = 0.003) compared to HDFs from HCs with 0.2 µM ATO. HDFs from volunteers with a diagnosis of ADHD incubated with 0.2 µM ATO resulted in different Bmal1 expressions at ZT16 (p = 0.030) and ZT28 (p = 0.019) compared to HC cultures incubated with 0.58 µM ATO. 0.20 µM ATO induced different Bmal1 expression between controls and ADHD group at ZT28 (p = 0.031). The expression of Per2 at ZT 12 (p = 0.015) was significant higher in HDF cultures incubated with 0.20 µM ATO compared to those exposed to 0.58 µM ATO. The expression was lower at ZT4 (p = 0.029) for HDF cultures from HCs with 0.20 μM ATO compared to ADHD participants without ATO , Cry1 at ZT0  and ZT28 , Per2 at ZT4  and Per3 at ZT 12 . A Bonferroni post hoc analysis revealed a significant lower expression in cultures incubated with 0.2 µM ATO compared to negative controls for Clock  and Per2 . The same effect was observed for the cultures incubated with 0.58 µM ATO for Cry1 . In contrast to this, the expression levels of Cry1 at ZT0 (p = 0.012), Per2 at ZT20 (p = 0.008) and Per3 at ZT12 (p = 0.017) were higher in HDFs incubated with ATO compared to the cultures without ATO. The Bmal1 , Per1  and Per3  expression differed between the two ATO concentrations in HDFs from HC. This was observed particularly at ZT16 for Bmal1 (p = 0.001) and ZT12 for period genes  , as determined by one-way ANOVA for Clock , Bmal1 , Per2  and Per3 . A Bonferroni posthoc correction revealed a significant higher expression in cultures incubated with 0.2 µM ATO compared to negative controls and those with 0.58 µM, particularly at ZT0 for Clock (p = 0.016) and Per3 (p = 0.007) and ZT28 for Bmal1 (p = 0.047). The expression was significant lower at ZT8 for Per3 (p = 0.043) and ZT16 for Bmal1 (p = 0.009) and Per2 (p = 0.047) in cultures incubated with 0.2 µM ATO compared to either negative controls or those with 0.58 µM ATO . In ADHD cultures incubated with 0.58 µM ATO, a positive correlation between chronotype and Per3 at ZT0  was observed. Additionally, in healthy participants group was a strong positive correlation for chronotype and clock genes, particularly at ZT0 for Per3 gene , and ZT16 for Bmal1  as well as Cry1 , respectively. In HC cultures incubated with 0.58 µM ATO, the strong positive correlation for chronotype with Bmal1 was shifted to ZT20 .The relationship between chronotype and circadian gene relative expressions was determined using Spearman’s rank order correlation. Strong positive correlations for chronotype and circadian genes were observed for Per3 immediately after synchronization at ZT0  and 16 h after synchronization for Bmal1 . A Bonferroni post hoc correction revealed a significant lower expression of Per3 (p = 0.018) and Bmal1 (p = 0.040) in healthy participants exhibiting neutral chronotype compared to those with moderate morning type. One-way ANOVA in the ADHD group revealed no statistical significant clock genes differences between chronotypes.Differences of clock gene expression levels among chronotype were assessed using one-way ANOVA. Gene expression in HDFs from healthy participants revealed a statistical significant difference between chronotypes for Bmal1 , Clock  and Per2 . Comparing healthy participants with definitive morning to those with moderate morning preference, Bonferroni post hoc correction showed significant lower Bmal1 expression levels at ZT8 (p = 0.038) and ZT20 (p = 0.044). The expression of Clock at ZT24 (p = 0.047) was significant higher among the healthy participants with moderate morning compared to those exhibiting definitive morning preference. When compared to neutral type the expression of Bmal1 at ZT20 (p = 0.006) and Per2 at ZT28 (p = 0.014) was significant different in healthy participants with definitive morning, and moderate morning chronotype, respectively. In ADHD cultures incubated with 0.20 µM ATO, one-way ANOVA revealed a statistical significant differences in gene expression between chronotypes for Per1  and Per2 . Bonferroni post hoc correction showed that the participants with definite evening preference had a higher Per1 at ZT8 compared to ADHD participants with neutral (p = 0.013) and moderate morning preference (p = 0.015). Similarly, different Per2 expressions levels were observed in ADHD participants exhibiting evening preferences at ZT4 (p = 0.025). Additionally, in participants with moderate evening preference, the expression of Per2 at ZT20 was significant higher compared to those exhibiting definitive evening (p = 0.012), neutral (p = 0.038) and moderate morning preference (p = 0.046). Higher concentration of ATO induced higher Bmal1 expression levels  in HDF cultures from ADHD participants with moderate evening chronotype, particularly at ZT12 after synchronization  compared to the participants with definite evening type.Exposure of HDFs cultures with ATO revealed differences between chronotypes. In HC cultures incubated with 0.58 µM ATO, one-way ANOVA revealed a statistical significant gene expression differences between chronotypes for Clock , Bmal1  and Per3  expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as from healthy participants with morning preference. ADHD participants with moderate evening chronotype presented significant lower Clock  and Bmal1  expression levels compared to HC with definitive morning and moderate morning chronotype, respectively. ADHD participants with neutral type revealed higher Per3 expression  than HC with moderate morning chronotype.When comparing the two study groups, significant different Clock, Bmal1 and Per2 gene expression.The results of the present study illustrate that attention-deficit hyperactivity disorder (ADHD) are associated to alterations in the circadian rhythm. It demonstrates that atomoxetine (ATO) impacts on circadian function, particularly the Ex vivo expression of circadian genes in fibroblasts has previously been demonstrated to be a useful approach to study circadian rhythms related to sleep/wake behavior . In the present study, there were no significant differences in BMI values across the two study groups.In the present study, the observed ATO effect in the ADHD group on Per1 and Per3 expression, 12 h after dexamethasone synchronization. Paradoxically, the expression of the two period genes was lower in cultures exposed to higher ATO concentration. This observations suggests that lower dose of ATO is inducing a phase delay of the Per1 and Per3 gene expression, as well as for Cry1. However, this effect was not observed in the cultures derived from ADHD participants. The expression and rhythm of all genes except Cry1 in the ADHD group adjusted to the healthy control group after ATO incubation. This effect is observed particularly for the lower ATO concentration. Higher concentration of ATO adjusts the expression of Clock gene toward the HC group, and shifts the expression of Bmal1 and alters the expression of Per3.Cultures from HC exposed to 0.20 µM ATO had a higher Bmal1 and Per2 genes. In ADHD patients and HC, Bmal1 expression differed between the two ATO concentrations 16 and 28 h after dexamethasone synchronization. Moreover, 0.20 µM ATO induced different Bmal1 expression between controls and ADHD group at ZT28. In HC, the expression of Per2 at ZT12 was significant higher in HDF cultures incubated with 0.20 µM ATO compared to those exposed to 0.58 µM ATO. The expression of Per2 was lower at ZT4 compared to negative control cultures from ADHD participants.We observed changes in the rhythmic expression of O’Keeffe et al.  reportedPer3 gene has been associated with chronotype, sleep homeostasis and various psychiatric disorders  in circadian genes were associated with core ADHD symptoms, increased evening-orientation and frequent sleep problem (Korman et al. havior An.A limitation of the study is the small sample size. Further studies with a higher number of participants are necessary. It is to mention, that no special cognitive testing was implemented in this study. In addition, the participants of the ADHD group took no medication before and during the study. For further studies, a connection between circadian disturbances, cognitive deficits and the effect of medication would be suitable.Bmal1, Per3 and Cry1 among the study participants, particularly after atomoxetine incubation at ZT0 and ZT16. Comparing the circadian preferences, statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO in ADHD participants exhibiting neutral and moderate evening preference, as well in healthy participants with morning preferences. ADHD participants with evening preference have higher Per2 expression 4 and 20 h after dexamethasone synchronization compared to the other chronotypes. We also observed an overexpression for Clock 16 h after synchronization for ADHD participants with moderate evening compared to HC with definitive morning preference. In summary, our results suggest that ATO influences circadian gene expression.In the present study, strong positive correlations for chronotype and clock genes were observed for


Introduction: Several investigations have been performed on insomnia symptoms in adult attention-deficit/hyperactivity disorder (ADHD). However, the relationship between insomnia disorder and adult ADHD has been neglected in research. The main objective of the current study is to analyze the differences between adult ADHD patients with and without insomnia disorder, in terms of ADHD clinical severity, medical and psychiatric comorbidity, psychopharmacological treatment, and quality of life.Material and Methods: Two hundred and fifty-two adult patients with ADHD  were evaluated with an exhaustive clinical and psychological evaluation protocol including semistructured interviews (for comorbidities and ADHD assessment) and symptom rating scales for ADHD. The diagnosis of ADHD and insomnia disorder was made according to DSM-5 criteria. Furthermore, the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale were administered.Results: Insomnia disorder was found in 44.4% of adult ADHD patients and was more common in combined presentation (64.3%) and in patients with more ADHD severity. Comorbidities , especially mood disorders (42%), anxiety disorder (26.8%), personality disorder (39.3%), and any substance use disorder (11.6%), were associated with a higher insomnia disorder prevalence. ADHD stimulant treatment was related to lower insomnia disorder compared to patients without medication, as well as ADHD stable treatment. Additionally, worse health-related quality of life was associated with insomnia disorder.Conclusion: Insomnia disorder is highly prevalent in adult ADHD and is related to higher ADHD severity and more psychiatric and medical comorbidities. Some stimulants and stable pharmacological ADHD treatment are associated with better outcomes of insomnia disorder. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by the presence of persistent symptoms of inattention and/or hyperactive–impulsive behavior , 2. The Insomnia disorder is one of the most frequent health problems in the adult general population, with an estimated prevalence between 6 and 15% , 5. HoweIn children, several researchers have reported a significant association between ADHD and sleep disturbances, using objective (actigraphy and polysomnography) and subjective studies –10. In aThe prevalence of insomnia symptoms in this population has a wide range between 43 and 85% –14, beinInsomnia symptoms and several psychiatric comorbidities have a bidirectional relationship. Mental comorbidities increase the risk of insomnia symptoms , and insThe relationship between ADHD treatment and insomnia is not well-established. Van Veen et al. reported that about 80% of untreated ADHD patients had sleep-onset insomnia symptoms . On the Most of the studies have focused on insomnia symptoms instead of insomnia disorder, with insomnia disorder in adult ADHD patients being frequently neglected in research. Hence, the main objective of the current study is to analyze the differences between adult ADHD patients with and without insomnia disorder, in terms of ADHD clinical severity, medical and psychiatric comorbidity, psychopharmacological treatment, and quality of life. We hypothesize that insomnia disorder would be associated with greater clinical ADHD severity and psychiatric comorbidities, an unstable ADHD treatment, and a poorer health-related quality of life.Furthermore, we intend to analyze the differences between patients with insomnia disorders and those with insomnia symptoms. It is hypothesized that insomnia disorder would be associated with greater clinical ADHD severity and psychiatric comorbidities.This cross-sectional study was conducted at the Adult ADHD Program of the Hospital Universitari Vall d'Hebron in Barcelona (Spain). Participants referred for the first time to the ADHD Program were recruited consecutively between April 2019 and February 2020 whether ADHD diagnosis was confirmed. This study was approved by the Clinical Research Ethics Committee of the Hospital Universitari Vall d'Hebron. All the participants voluntarily agreed to get involved in the study and did not receive any financial compensation.The participants fulfilled the following inclusion criteria: were over 18 years, met ADHD criteria according to DSM-5, accepted to participate, and signed the informed consent. Those patients diagnosed with a sleep disorder other than insomnia disorder , intellectual disability (intelligence quotient < 70), or any medical condition that could explain the symptoms of ADHD  were excluded.Conners' Adult ADHD Diagnostic Interview for DSM-IV part I (CAADID-I) (kappa index concordance was 0.88 (The AADID-I)  is a semwas 0.88 .Diagnostic Interview for ADHD in Adults (DIVA 2.0) (The IVA 2.0)  consistsIVA 2.0) .Conners' Adult ADHD Rating Scales—Long Version (CAARS) is a 66-item self-reported instrument designed to assess ADHD in adults and has high degrees of sensitivity and specificity, with an overall diagnostic efficiency rate of 85% . It is a self-administered 18-item validated scale that provides a consistent way for clinicians to diagnose ADHD according to the DSM-5 criteria, with high sensitivity (81.9%) and specificity (74.7%) and a kappa coefficient of 0.78  was used. It is a reference scale in the evaluation of the disorders severity and has also shown good psychometric properties  and Axis-II (SCID-II) (The SCID-II)  were useSCID-II) .Beck-II Depression Inventory II (BDI-II) was administered for measuring depressive symptomatology (The matology . This rematology .State-Trait Anxiety Inventory (STAI) was used to measure anxiety (both trait and state) (The d state) . It is od state) .Barratt Impulsiveness Scale (BIS-11) was used for measuring trait impulsivity as this instrument provides a total score and three subscale scores , and therefore, this scale measures impulsivity as a multidimensional construct with good reliability  (The  = 0.83) .Insomnia Severity Index (ISI) which evaluates insomnia severity in the last month and includes several sleep dimensions: severity of sleep onset, sleep maintenance, early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by the sleep difficulties . This is a 19-item self-reported instrument that assesses sleep quality and its disturbances during the last month  which is a self-reported questionnaire with eight items that allows measuring the subject's overall level of daytime sleepiness  . This inThe Adult ADHD Program of the Hospital Universitari Vall d'Hebron is a multidisciplinary and comprehensive program that evaluates and treats referred patients from primary care centers, community mental health centers, and addiction treatment units. Once referred to the ADHD Program, a complete assessment of the patient is carried out to establish the diagnosis and the treatment.For the current study, the evaluation process consisted of five visits conducted by trained staff specialized in ADHD and sleep disorders (psychiatrists and psychologists). At the first visit, the psychiatrist obtains a complete medical history, including a clinical approach for ADHD and insomnia disorder. Besides clinical assessment, a standardized evaluation with validated instruments for ADHD  and insomnia disorder  was conducted during the first visit. At the next three visits, the psychologist carried out the CAARS, ADHD-RS, STAI, BDI, SF-36, SCID-I, and SCID-II interviews. Finally, at the fifth visit, the psychiatrist responsible for the patients reviewed all the information and communicated the final diagnosis to the patient at the end of the study. The diagnosis of insomnia disorder and ADHD was made by the psychiatrist according to DSM-5 criteria. Whether the diagnosis of ADHD was confirmed, the patient was offered to perform a psychiatric and psychological treatment and follow-up in the program .The Wechsler Adult Intelligence Scale-IV (WAIS-IV) was used to assess patients' intelligence quotient (IQ).t-test and ANOVA were used for quantitative variables. Bonferroni correction for multiple testing was used in order to minimize type I error. Finally, a logistic regression analysis was conducted using the variables that remained statistical significance Bonferroni correction. In order to avoid collinearity, variables related to sleep were not included in the multivariate analyses. The dependent variable was insomnia disorder diagnosis (0 = no insomnia disorder and 1 = insomnia disorder). A conditional entrance method was used to select variables in the model. All statistical hypotheses were two-sided and a value of p < 0.05 was considered statistically significant.Bivariate and multivariate analyses were executed using SPSS version 20 for Windows. First, a descriptive analysis of all variables as percentages, means, and standard deviations was conducted. To compare ADHD patients with and without insomnia disorder, chi-square test was used for nominal variables and Student's During the recruitment period, 252 patients  met the inclusion criteria and accepted to participate in the study. In order of frequency, the combined presentation of ADHD was the most common (56.7%), followed by the inattentive presentation (39.7%) and hyperactive/impulsive presentation (3.6%). Regarding insomnia, 44.4% of patients met the criteria for insomnia disorder and 63.9% of the total sample participants had insomnia symptoms.T: 1.467; p = 0.144) and those without that disorder (103.42 ± 13.10) and neither also when family psychiatric records were compared. Any medical record and high body index mass (BMI) were related to a higher prevalence of insomnia disorder. Regarding specific medical comorbidities, due to the small sample size, some medical diseases could not be statistically analyzed. However, it was observed that the group with insomnia disorder had a higher prevalence of pain syndrome compared with the group without insomnia disorder (18.9 vs. 13.2%) but a lower prevalence rate regarding diabetes mellitus (1.9 vs. 7.9%) and arterial hypertension (3.8 vs. 18.4%). No differences were found regarding other comorbidities, including cardiac, endocrine, gastrointestinal, respiratory, and neurological diseases. Similarly, several pharmacological treatments for those medical diseases were not analyzed because of small size. In any case, non-opioid analgesics were more used in patients with insomnia disorder (29.5 vs. 19.4%), while a fewer use of antihypertensive (4.5 vs. 22.6%) and oral antidiabetic medications (2.3 vs. 9.7%) was observed. No differences were found for other medication categories for medical conditions  and psychiatric disorders .Sociodemographic, clinical, and psychometric variables are presented in ADHD patients with any psychiatric comorbidity are more likely to present insomnia disorder, especially those who currently have mood disorders, anxiety disorder, any SUD, and any personality disorder . Congruently, ADHD patients with insomnia disorder had higher BDI-II, STAI, and BIS-11 scores. Finally, a worse HRQoL  was observed in ADHD patients with insomnia disorder .Regarding ADHD variables and insomnia disorder, it was observed that insomnia disorder was most frequently presented in patients with the combined presentation of ADHD or with higher severity of ADHD . Patients who were in any pharmacological treatment had less prevalence of insomnia disorder . Longer periods of stable treatment were associated with lower rates of insomnia disorder .Regarding sleep assessment, patients with insomnia disorder presented higher scores on the ISI scale and the PSQI. When the PSQI subscales were analyzed, statistically significant results were reported. Likewise, patients with insomnia disorder had greater daytime sleepiness reported on the ESS. Finally, both the prescription of hypnotic medications and their number were higher in patients with insomnia disorder. No differences were found among the different groups of hypnotic medications and in the concomitant prescription of other psychotropic drugs .F = 8.426; p ≤ 0.001), while in older patients, maintenance insomnia (40.78 ± 12.80), mixed insomnia (41.70 ± 11.43), and early awakening insomnia were the predominant phenotypes (43.50 ± 6.36).When the different insomnia phenotypes were analyzed, sleep-onset insomnia was the most frequent (32.9%), followed by sleep maintenance insomnia (31.0%), mixed insomnia (25.4%), and early morning awakening (11.5%). These phenotypes were compared based on sociodemographic, ADHD, and psychiatric comorbidity characteristics. No statistically significant differences were found, except for age. Younger age was associated with sleep-onset insomnia . On the other hand, no differences were found comparing personality disorders and SUD variables. Likewise, no differences were reported considering the different ADHD medications . The second logistic regression model analyzed medical and psychiatric comorbidities. In this model, current psychiatric disorders, previous history of anxiety disorders, and SUD were independently related to insomnia disorder . Finally, the relationship between psychological features and insomnia disorder was explored by using the variables that were statistically significant in the bivariate analysis. Low scores on physical and mental components of HRQoL were independently associated with a higher prevalence of insomnia disorder .Finally, three logistic regression models were conducted using the variables that retained statistical significance after Bonferroni correction and considering insomnia disorder as the dependent variable . The firIn line with our hypothesis, the current study highlights that ADHD and insomnia disorder comorbidity in adults is highly prevalent. Moreover, patients who suffer both conditions are more clinically severe. Therefore, our hypothesis is confirmed as patients are characterized by a greater severity of ADHD, more psychiatric comorbidities, an unstable ADHD treatment, and a poorer health-related quality of life.In the current sample, 44.4% of patients met the criteria for insomnia disorder according to DSM-5 and 63.9% had insomnia symptoms. This high prevalence of insomnia disorder and insomnia symptoms in ADHD patients is in line with the prevalence of insomnia symptoms previously reported to be between 43 and 80% , 12, 14.Current results on ADHD presentations and insomnia disorder were similar to previous studies that describe combined presentation is more associated with insomnia symptoms . HoweverWhen analyzing sociodemographic variables, only unemployment was significantly associated with more risk of insomnia disorder. These results have been already reported in previous studies, suggesting that unemployment is associated with poorer mental health and lower physical activity, which could cause insomnia . Note thIn line with other studies, patients with insomnia disorder had higher BMI . ObesityCongruently with prior research , 56, psyRegarding pharmacological treatment, stimulant medications have shown to have a greater effect size on ADHD symptoms compared with atomoxetine . ProbablOur results are congruent with the studies that indicate that pharmacological treatment would improve insomnia symptoms , even inConcerning insomnia phenotypes, when considering the different risk factors, only age had statistically significant association. As previous studies reported , 63, youThe current analysis exposed a higher incidence of insomnia disorder in patients who use screens in the half-hour before bedtime. Exposure to blue light from these devices has been associated with a greater alteration of circadian rhythms, as well as a higher prevalence of sleep-onset insomnia and poorer sleep quality . Some auRegarding health-reported quality of live, insomnia disorder was independently related to a negative impact on both physical and mental components of HRQoL. Only patients without insomnia disorder presented normal scores in the physical component of HRQoL. Physical and mental components were affected in patients with insomnia disorder compared with normative data . TherefoFinally, when characterizing the insomnia symptoms group, our results point that patients with insomnia symptoms had lower clinical severity of ADHD according to the ADHD-RS and a greater number of months of stability of the ADHD treatment. Furthermore, our results showed lower psychiatric comorbidity and better mental component of the HRQoL in patients with insomnia symptoms when they were compared with patients with insomnia disorder. These results, which support our hypothesis, could contribute to identify the factors of severity of ADHD, psychiatric comorbidity, and quality of life that could be associated with the transition between both clinical categories: insomnia disorder and insomnia symptoms.This study should be analyzed regarding its limitations. First, objective or electrophysiological measures of sleep such as polysomnography or actigraphy were not used. The use of these instruments would provide more strength to the results. Second, the cross-sectional design does not allow analyzing the bilateral association. Third, the effect of pharmacological prescriptions for the treatment of psychiatric comorbidities, specifically mood disorders, was not controlled. Fourth, except for the use of screens before sleeping, no other patient sleep hygiene measures were recorded and neither do the patients diet characteristics. On the other hand, this research has important strengths. To the best of our knowledge, this would be the first published study evaluating the relationship of adult ADHD with insomnia disorder according to the diagnostic criteria of DSM-5 in adult patients. Furthermore, to avoid confounding factors, those patients who suffered any other sleep disorder that could be confused with insomnia disorder  were excluded from the study. Finally, we must emphasize that the sample has included naive patients and treated patients, which allows us to better assess the impact of the treatment, as well as to bring the results closer to the reality of clinical practice.The current study points out that adult ADHD patients with insomnia disorder have a worse clinical presentation due to a higher ADHD severity, more comorbidities, and worse quality of life. These results may contribute to a better understanding and clinical approach of insomnia disorder in the context of a wide and heterogeneous pathology such as ADHD, by allowing to identify some of the sociodemographic, clinical, and comorbidity characteristics associated with both disorders when they occur together.The datasets generated for this study can be available on request to the corresponding author. Part of the data may not be allowed for distribution to others than the research group that conducted the study as may violate ethical and/or legal regulations of written consent.The studies involving human participants were reviewed and approved by Clinical Research Ethics Committee of the Hospital Universitari Vall d'Hebron. The patients/participants provided their written informed consent to participate in this study.CF, CD, LG-L, and JR-Q conceived, designed, and supervised the study. CF, CD, VR, and MC contributed data or analysis tools. CF, VR, and MC collected the data. CF, CD, LG-L, and RP-A performed the data analysis. CF, CD, VR, LG-L, RP-A, MC, and JR-Q wrote the manuscript. JR-Q secured funding for the study. All authors contributed to the article and approved the submitted version.CF has received fees to give talks for Shire/Takeda and Rubio. VR has received travel awards (train tickets + hotel) for taking part in psychiatric meetings from Shire in the last 3 years. LG-L has received fees to give talks for Janssen-Cilag, Lundbeck, Servier, Otsuka, and Pfizer. RP-A has received fees to give talks for Exeltis, Lundbeck, MSD, Mundipharma, and Takeda. JR-Q was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogui, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogui, Bial, Medice, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


As previous studies have reported abnormalities in the iron indices of peripheral blood and hyperechogenicity of the substantia nigra (SN) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), we aimed to examine the same in adults with ADHD using transcranial Doppler sonography (TCS). In addition, we compared the iron indices and TCS findings before and after methylphenidate (MPH) treatment. A total of 39 participants aged ≥19 years  were recruited from Kyung Hee University Hospital between October 2018 and September 2019. All subjects were clinically evaluated based on the ADHD diagnostic criteria in the DSM-5, the Adult ADHD Self-Report Scale, and the Diagnostic Interview for ADHD in Adults (DIVA-5). Further, the iron indices including serum iron, ferritin, and mean platelet volume were determined. Additionally, TCS focused on the midbrain and echogenicity of the SN was conducted. Follow-up for all items was conducted for five ADHD patients after MPH treatment. Patients with ADHD had significantly lower education levels (number of years) than controls. There were no statistically significant differences in serum iron indices or the echogenic area between ADHD and control groups. Further, there were no significant changes in iron indices or TCS findings after MPH medication. Unlike previous studies, this study showed no differences between patients with ADHD and controls. Therefore, it is important to determine if these null findings were due to different target populations (children vs. adults) or other factors, including ADHD subtypes.  There is considerable variation in the persistence rate of attention-deficit/hyperactivity disorder (ADHD) from childhood to adulthood, with estimates ranging from 15% , dependiIron has been implicated in brain function and dopaminergic activity, and abnormalities in iron levels have been used to explain the etiology of ADHD . Given tAlthough magnetic resonance imaging (MRI) can be used for the measurement of brain iron content , transcrAs previous studies using TCS have mostly focused on children and adolescents with ADHD, this study targeted adults with ADHD to determine the correlation between the iron indices of peripheral blood and echogenicity of the SN using TCS. Further, we examined the changes in biological indices after psychostimulant treatment.This prospective case–control study was conducted between October 2018 and September 2019. Thirteen patients aged ≥19 years who were newly diagnosed with ADHD were enrolled during their initial visit at Kyung Hee University Hospital. Subjects in the ADHD group were drug naïve or had not used anti-ADHD drugs in the previous 3 months. Age- and sex-matched healthy controls were recruited through offline and online portals at Kyung Hee University Hospital. All participants were evaluated by clinicians (GHB and SYL) using the Adult ADHD Self-Report Scale, Korean version (K-ASRS) and the Diagnostic Interview for ADHD in Adults (DIVA-5). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition . The excThe ASRS is an 18-item self-report scale based on the DSM-IV symptom criteria developed by the World Health Organization , which wThe DIVA is a semi-structured interview tool for diagnosing ADHD in adults, which is available from the DIVA foundation website . DIVA-5 The following indices related to iron metabolism were used: serum iron, ferritin, transferrin, total iron-binding capacity (TIBC), hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean platelet volume (MPV). We used a color-coded duplex ultrasound system equipped with a 2.0–2.5 MHz phased array transducer . Using a low frequency of 2.0–2.5 MHz makes it easier for ultrasound to pass through the temporal bone in the skull. Ultrasound parameters included a penetration depth of 16 cm and a dynamic range of 45–50 dB. The examination with the TCS probe was performed through the preauricular acoustic bone window, on both the right and left sides. The visualization of the target structures may depend on the quality of the temporal acoustic bone window. The SN was identified as a tie-shaped echogenic signal within the butterfly-shaped mesencephalic brainstem. To check hyperechogenicity, the sonographer marked areas manually but measurements were performed automatically . TCS resThe CGI-S is a seven-step scale for measuring the severity of symptoms (1 = no disorder to 7 = severe disorder) and the CGI-I is a seven-step scale for measuring improvements in symptoms  . Once the subjects were finalized, blood tests were performed to measure iron composition indicators followed by TCS. For the ADHD group, methylphenidate (MPH) treatment was initiated if a patient opted for it, and no placebo was administered to the control group. In the ADHD group, for patients receiving MPH, blood tests and TCS were performed again when the CGI-I indicated “very much” or “much improved” (CGI-I ≤ 2) . The priWritten informed consent was obtained from all subjects prior to their participation in the study. The study protocol was approved by the Institutional Research Board of Kyung Hee University Hospital (KMC IRB 2018-02-007), and followed the ethical standards of the Declaration of Helsinki.p < 0.05. The comparison of the demographic characteristics, iron indices, and TCS findings between the ADHD and control groups was performed using the Wilcoxon rank-sum test and the chi-square test. A multiple generalized linear model was used to obtain results which were adjusted for age and education level. The comparison before and after MPH treatment in patients who underwent follow-up tests was performed using the Wilcoxon signed-rank test. SAS 9.4  was used for statistical analysis, and the significance level was set at There were 13 subjects  in the ADHD group and 26 subjects  in the control group. p = 0.001) than controls (p = 0.0095) and women (p = 0.0024) in the ADHD group had lower education levels than those in the control group.Patients with ADHD had significantly lower education levels , or TCS findings (midbrain area (right and left) and echogenic area of the SN (right and left)) between the two groups . In addiAmong the 13 subjects in the ADHD group, five subjects had to be excluded from the follow-up tests because of early dropout and three subjects were excluded because they were prescribed additional psychotropic medication during the study period due to depression, mood swing, or insomnia. Finally, five subjects took the MPH medication only and completed the follow-up tests . No signIn this study, none of the iron-related indicators showed a significant difference between the ADHD and control groups, regardless of sex. These results were not consistent with a previous meta-analysis of iron status in children with ADHD . HoweverAs variations in systemic iron levels in ADHD patients have been reported, recent studies have suggested that iron levels in the brain, rather than systemic iron levels, may be associated with the pathophysiology of ADHD in children . A meta-The influence of comorbid psychiatric and physical conditions may be one of the reasons why the results of this study differed from those of previous studies. Although the clinician interviewed all participants, it may have been difficult to exclude both physical and neurological diseases. Serum iron levels can be influenced by several conditions, including inflammation, obesity, Tourette syndrome , and epiYouth with ADHD showed a significantly larger SN echogenic size than healthy control children ,11. KrauThere is not enough data on the association between ADHD medication and brain function or structural changes, especially in adult patients. While evidence suggests that iron supplementation reduces the severity of ADHD symptoms, brain imaging data before and after iron supplementation are insufficient . It has In this study, there were no significant differences in the echogenic area in the SN in follow-up tests conducted after MPH treatment. Similar studies cannot be found in the literature, which limits the interpretation of our results. Moreover, polypharmacy including ADHD drugs, is frequently prescribed for adult ADHD patients due to comorbid psychiatric and medical conditions . TherefoThis preliminary study has several limitations. First, the results of this study, especially the follow-up tests in patients receiving medications, should be very carefully interpreted considering the different dosages, durations, and types of medications, and the small number of subjects with no control group. Second, although TCS is convenient to use, there are some disadvantages in using this technique—the signal and noise of TCS are influenced by individual differences and the results may vary depending on the proficiency of the sonographer. Currently, the results from TCS or iron-related laboratory tests are not sufficient and are inconsistent for use as biomarkers for ADHD, and cannot be applied to clinical practice. Nonetheless, future research should yield valuable results based on this study design through the recruitment of sufficient numbers of patients and appropriate control of the medications used, as well as the use of control groups. Although the results of this study contradict the results of previous studies and did not demonstrate any significant difference in the echogenicity of the SN between patients with ADHD and controls, this is the first study to examine the echogenicity of the SN in adults with ADHD and the effects of psychostimulant treatment on the midbrain and SN. The serum iron indices and the neuroimaging findings of TCS reported in this study did not corroborate with those reported in previous studies involving children and adolescents. However, this study included adult subjects. Therefore, it is necessary to confirm the findings of this study using larger samples. Further, the role of intracerebral networks related to the iron pathway in the pathophysiology of ADHD in adults should also be explored.


Measure compliance with National Institute for Health and Care Excellence (NICE) recommendations in four Adult CMHT'sGuide further service development.We audited the case notes of 20 patients each currently under care of 9 General Adult Consultants across 6 CMHT's in East side of North Wales against NICE standards using an adapted version of the ADHD audit support tool.My role in the Project & How does this represent my practice?I was the audit and overall lead for this projectI formulated the audit tool and registered my project with Audit Registration Team.I lead data collection and compilation of results.Overall, this is the first audit of Adult ADHD Services in East side of North Wales.It established good compliance with NICE guidance for assessment and treatment.NICE has expressed the need for full mental health and social assessment including full history and physical examination prior to the drug treatment.Good compliance was observed in using & documenting Diagnostic Criteria (DSM-IV and/or ICD-10).There were deficiencies in conducting or arranging recommended physical examination & side effect monitoring.Drug treatment was the first line of treatment in the majority of cases.Antipsychotics were used in some patients referred for ADHD assessment, despite the fact that NICE has ruled out the use of antipsychotic drugs in treatment of core symptoms of ADHD.Prevalence of Adult ADHD clinician case load in Wrexham and Fintshire Counties.Diagnosis of Adult ADHD according to ICD 10 & DSM IV Guidelines.Pre treatment screening of physical health for ADHD patients.Side effects monitoring of patients on stimulant medications.The finding highlights the need for more effort in educating clinicians about safety and effectiveness of antipsychotics in ADHD.Comprehensive treatment programmes that address psychological, behavioural, educational and occupational needs should be established.Development of local ADHD Clinics, support groups and in partnership with the voluntary sector should be encouraged.It is important that mental health professionals receive appropriate training in assessment, management & monitoring of ADHD patients with co morbid substance use disorder and other mental illnesses.BETSI Health Board to participate in national Prescribing Observatory for Mental Health (POMH-UK) Quality Improvement Programme (QIP) focusing on prescribing for ADHD in children, adolescents & adults.


Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that has a unique status of a quintessentially neuropsychiatric condition at the interface of neurology (movement disorder) and psychiatry . However, the behavioral and emotional profile has seemed to be neglected in the literature thus far. This study aimed to investigate the behavioral and emotional profile of TS.A total of 124 patients aged 6–16 years with TS were included in this study, including age- and sex-matched health control, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and major depressive disorder (MDD) groups. The Child Behavior Checklist (CBCL) was used to screen the behavioral and emotional profile of the TS and other compared groups. The Yale Global Tic Severity Scale (YGTSS) was used to assess TS tic severity. Analysis of variance (ANOVA) was used to investigate the difference between the TS and other compared groups.p > 0.05). However, positive correlations were identified between functional impairments  and thought problems (TP) and rule-breaking behavior (RBB). Based on the eight-factor profile of the CBCL, TS showed a similar profile to MDD but different from ADHD and OCD, which showed similar profiles.The results showed that the eight factors of the CBCL had no association with motor tics, vocal tics, or tic severity (Based on the assessment of the CBCL of TS, it was found that “pure” TS might show fewer behavioral and emotional problems than OCD, ADHD, and MDD. Similar behavioral and emotional profiles were identified between TS and MDD, but not OCD and ADHD. More attention needs to be paid to the thought problems and rule break problems in the CBCL in the screening stage, which might have a potential influence on the functional impairments of TS. Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple motor tics and one or more vocal tics that persist for at least 1 year . It shouTo the best of our knowledge, the behavioral and emotional symptoms of TS include attention problems, aggressive behavior, anxiety/depressive symptoms, obsessive-compulsive symptoms, and so on . Most ofFurthermore, the comorbidities of TS, such as ADHD, OCD, and MDD, suggest that there is an overlap between TS and these mental disorders . Most stThe Child Behavior Checklist (CBCL) is one of the most important and stable tools for identifying the behavioral and emotional profiles of mental disorders , 18. It Therefore, this study aimed to investigate the behavioral and emotional profile of “pure” TS. Furthermore, we compared the differences in behavioral and emotional profiles between TS and other mental disorders ; the CBCL was used to present these differences. We hypothesize that TS may show different behavioral and emotional profiles when compared with OCD, ADHD, and MDD.Children and adolescents (aged 6–16 years) with TS participated in this study. All participants were recruited from the Department of Psychiatry in Beijing Children's Hospital in China from 1 October 2019 to 1 September 2021. To identify patients with “pure” TS, the following criteria had to be met: (1) aged between 6 and 16 years, (2) met the Tourette syndrome diagnostic criteria according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), (3) no central nervous system diseases or intellectual disability, and (4) no comorbidities of other mental disorders. Age- and sex-matched groups with MDD, OCD, and ADHD as well as healthy controls (HCs) were also recruited. To identify the patients with “pure” MDD, OCD, and ADHD, the criterion was that all patients in these groups should not have comorbidities with other mental disorders. For example, if the included patients belong to the MDD group, they should not have OCD, ADHD, TS, or other mental disorders. The HC group did not have any mental disorders.This study was approved by the ethics committee of Beijing Children's Hospital of Capital Medical University, and written informed consent was obtained from the legal guardians of the participants or their parents.The YGTSS is a semi-structured interview developed to assess the nature and severity of motor and vocal tics , 26. TheThe CY-BOCS is a semi-structured scale rated by a clinician. It was used to assess the severity of obsessive and compulsive behaviors during the previous week in patients with OCD aged 8–16 years . The obsThe DSRSC was used to assess depressive symptoms in young children aged 8–14 years. It measures the direction of disturbances felt in the past week . Three oThe SNAP-IV consists of 26 items rated on a 4-point scale  . Three sThe Chinese version of the CBCL contains 118 specific behavioral and emotional problem items and two open-ended items . Each syt-test and the percentage of boys using a chi-square test. Second, the mean, standard deviation (SD), kurtosis, and skewness of the CBCL and its subscales were calculated for the TS group. Third, we calculated the Pearson correlation between the YGTSS and CBCL. Fourth, multivariate analysis of variance (MANOVA) was used to compare the CBCL and its subscales in different groups . MANOVA is a procedure for comparing multivariate sample means. As a multivariate procedure, it is used when there are two or more dependent variables and is often followed by significance tests involving individual dependent variables separately  indicated significance against the null hypothesis.Statistical analyses were performed using the Statistical Package for the Social Sciences . First, we compared age using a parately . Bonferrn = 127), OCD (n =128), MDD (n = 127), and HC (n = 130) groups. For more details, see A total of 150 patients with TS were identified, but 26 were excluded due to comorbidities of other mental disorders. Finally, 124 patients with TS were included in the TS group. Furthermore, the age- and sex-matched groups included ADHD (p = 0.97). For the percentage of males, the TS group was 70.97%, ADHD group was 70.08%, OCD group was 70.31%, MDD group was 69.29%, and HC group was 68.46%; there was no significant difference among these groups . The mean years of education of the patients in these groups were 4.36 ± 1.87 years (TS), 4.45 ± 2.25 years (ADHD), 4.58 ± 2.21 years (OCD), 4.48 ± 2.88 years (MDD), and 4.46 ± 2.19 years (HC). For the years of education, no significant age differences were identified in these groups (p > 0.05). The duration of illness (years) of the patients in these groups was 2.37 ± 1.89 years (TS), 2.48 ± 1.04 years (ADHD), 2.59 ± 1.45 years (OCD), 2.48 ± 1.06 years (MDD), and 2.46 ± 1.38 years (HC). For the duration of illness, no significant age differences were identified in these groups (p > 0.05).The mean age of the patients in these groups was 10.37 ± 1.91 years (TS), 10.48 ± 2.74 years (ADHD), 10.59 ± 2.45 years (OCD), 10.48 ± 3.06 years (MDD), and 10.46 ± 2.38 years (HC). No significant age differences were identified in these groups . The CY-BOCS score of the OCD group was 15.36 ± 4.45. Three subscales of SNAP-IV scores in the ADHD group were 1.75 ± 0.43 (inattention score), 1.83 ± 0.52 (hyperactivity/impulsivity score) and 0.83 ± 0.35 . The DSRSC score in the MDD group was 21.31 ± 5.83.p > 0.05). However, positive correlations were identified between the function impairments (YGTSS) and the TP and RBB  , TS, OCD, ADHD and MDD groups   showed the following relationships with respect to CBCL profiles between the groups: TS > HC (p < 0.001), TS < OCD (p = 0.001) and ADHD (p < 0.001). No significant differences were identified between the TS and MDD groups (p = 0.530). For more details, see First, we compared the total CBCL scores of all the groups and found that F was 53.55 (p < 0.001), but no significant difference was identified among the TS, ADHD, OCD, and MDD groups. The SP factor showed the same pattern as SC, TS > HC (p < 0.001), but no significant differences were identified among the TS, ADHD, OCD, and MDD groups. For the A/D factor, TS > HC (p < 0.001), TS < OCD (p = 0.003) and ADHD (p = 0.006). The W/D factor showed the same pattern as A/D, TS > HC (p < 0.001), TS < OCD (p < 0.001) and ADHD (p = 0.004). The TP factor also showed the same pattern as A/D and W/D, TS > HC (p < 0.001), TS < OCD (p = 0.024) and ADHD (p = 0.016). The AP factor also showed the same pattern as A/D, W/D, and TP, TS > HC (p < 0.001), TS < OCD (p = 0.029) and ADHD (p = 0.001). For the RBB factor, TS > HC (p < 0.001) and TS < ADHD (p = 0.023). For the AB factor, TS > HC (p = 0.012), and TS < OCD (p < 0.001), ADHD (p < 0.001), and MDD (p = 0.002). For more details, see Second, multivariate analysis of variance was used to compare the eight factors of the CBCL subscales in different groups . For the SC factor, TS > HC  and an Old Group (12–16 years old). We also used the radar chart to present the CBCL profiles of these two groups based on the T-scores. There might be a higher score on the 8 subscales of the CBCL in the Old Group than in the Young Group. For more details, see This study aimed to compare the behavioral and emotional profile of “pure” TS with other mental disorders. The results showed that there was no correlation between tic symptoms and behavioral and emotional problems in “pure” TS. However, TP and RBB might have a potential influence on TS function. The “pure TS” group showed higher behavioral and emotional problems than the HC group and the same level of severity of behavioral and emotional problems as the MDD group. The “pure” OCD and ADHD groups showed higher-level severities of behavioral and emotional problems than the TS group. Moreover, the difference between the TS and OCD groups was mainly in the dimensions of A/D, W/D, TP, AP, and AB. The difference between the TS and ADHD groups was mainly in the dimensions of A/D, W/D, TP, AP, RBB, and AB. The difference between the TS and MDD groups was mainly in the AB dimension. TS, OCD, ADHD, and MDD showed the same levels of SC and SP. These results indicate that the “pure” TS might have a similar behavioral and emotional profile to “pure MDD” but a different profile compared to “pure” OCD and ADHD.In the present study, it was found that the TS group might show a similar behavioral and emotional profile to the MDD group at the behavioral level. Rizzo et al.  reportedFurthermore, in the present study, we also found a difference in AB between “pure” TS and MDD. Compared with MDD, OCD, and ADHD, “pure” TS showed less aggressive problems. Aggressive behavior can be found in young patients with MDD , ADHD 3, 39, andIn the present study, we found confirmed differences between TS and ADHD at the behavioral level. “Pure” ADHD might present more ADHD-related behavioral problems , which is different from tic symptoms. Furthermore, ADHD-related behavioral problems might also lead to emotional problems, which might be the reason why ADHD showed higher scores for A/D and W/D than TS. Furthermore, similar results were obtained when TS was compared with OCD. The OCD group showed higher levels of behavioral problems in AP, AB, RBB, and TP, as well as emotional problems in A/D and W/D. However, for the RBB, the TS and OCD groups showed similar scores. It should be noted that ADHD and OCD were the two most common comorbidities for TS, and both tend to persist . Both thNotably, we identified the relationship between TP and the function of TS, which indicates that this dimension of behavioral and emotional problems might influence the functional impairment of TS. Although TP is clinically useful for identifying psychotic symptoms in children, it also includes items for the assessment of obsessive thoughts and compulsions, self-harm, picking at parts of the body, and more . These iRBB has been shown to be associated with antisocial behavior problems, which are key factors in the development of youth violence and aggression , 49. ThiCompared to RBB, TP had less significant kurtosis. Therefore, TP may be more closely related to TS than RBB, and compulsivity indicated by TP may be a feature of TS, even if OCD is not comorbid.Overall, in the present study, we found that “pure” TS might show fewer behavioral and emotional problems than OCD and ADHD. Similar behavioral and emotional profiles were identified between TS and MDD, but not OCD and ADHD. These results indicate that comorbidities (such as OCD and ADHD) might make the behavioral and emotional profiles more complex. Aggressive problems might be an important factor in distinguishing “pure” TS from OCD, ADHD, and MDD. Furthermore, we need to pay more attention to TP and RBB problems in the screening stage of TS, which might have a potential influence on the functional impairments of TS.This study has two limitations. First, a limited number of participants were included in this study. A larger sample size and follow-up studies of behavioral and emotional profiles for TS are needed to confirm these results. Second, anxiety disorders are also a common comorbidity of TS but were not included in this study. Third, information about the medication used is absent. Previous studies have found that the medicine used for the treatment of tic symptoms might also influence behavioral and emotional symptoms –52. TherThis study explored the behavioral and emotional profiles of TS. Similar behavioral and emotional profiles were identified between TS and MDD, rather than OCD/ADHD. Aggressive behavior might be an important factor in distinguishing “pure” TS from OCD, ADHD, and MDD. More attention needs to be paid to the TP and RBB problems of the CBCL, which might have a potential influence on the functional impairments of TS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committees of Beijing Children's Hospital of Capital Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YC and YiL took the initiative. JC and YaL finished the data collection. YiL performed the data analysis and finished the draft. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (NSFC) under Grant No. 82001445 and 82171538, the Beijing Natural Science Foundation under Grant No. 7212035, and the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority, No. XTYB201802.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.