Task switch protocols are frequently used in the assessment of cognitive control, both in clinical and non-clinical populations. These protocols frequently confound task switch and attentional set shift. The current study investigated the ability of adult ADHD patients to shift attentional set in the context of switching tasks.We tested 38 adults with ADHD and 39 control adults with an extensive diagnostic battery and a task switch protocol without proactive interference. The experiment combined orthogonally task-switch vs. repetition, and attentional set shift vs. no shift. Each experimental stimulus had global and local features , associated with corresponding attentional sets.ADHD patients were slower than controls in task switch trials with a simultaneous shift of attention between global/local attentional sets. This also correlated significantly with diagnostic scales for ADHD symptoms. The patients had more variable reaction times, but when the attentional set was kept constant neither were they significantly slower nor showed higher task switch costs.ADHD is associated with a deficit in flexible deployment of attention to varying sources of stimulus information. Alth. Alth8])ADHD-related impairment in conditions associated with TS has been reported in several studies e.g., –13). In . In 13])Findings obtained in a recent Eriksen Flanker Task study  involvinBecause in selective attention tasks, such as Eriksen Flanker, the target stimulus contains all information needed for successful task performance, these tasks can be accomplished by maintaining a strongly focused state of attention regardless of contextual changes. Deficits in flexible attentional adjustment should be associated with more detrimental consequences, however, if task-relevant stimulus information must be extracted from frequently changing stimulus features. As noted above, this is the case in TS studies which involve tasks associated with different target stimulus features. In light of the fact that tasks combined in TS experiments are associated with a multitude of additional processing differences , however, it is conceivable that TS performance can be accomplished by relying on biasing processing independently of stimulus perception .Standard TS protocols may thus not constitute an optimal means to assess attentional adjustment. To investigate a possible impairment in adjusting the set of stimulus selection, we followed the approach of . This stAssuming that ADHD is associated with a particular deficit in flexible adoption of (task-specific) sets of stimulus selection one would predict particular enhancement of switch costs and congruency effects in the mixed levels condition for patients with ADHD compared to controls. By contrast, switching between the same tasks should not be particularly impaired when target levels are kept constant.Interpretation of task switch costs in terms of executive functioning is usually rendered difficult by stimulus-specific effects of interference between tasks. TS performance seems particularly impaired if a stimulus is processed that was previously presented in the context of the other task , possibM age = 36.14 years, SD = 12.17; 17 women) with a diagnosis of ADHD as their primary disorder, were recruited in a Hamburg neurological outpatient practice which is specialized in the diagnosis and treatment of ADHD in adults. During a regular appointment in the practice patients were informed about the possibility to participate in the experiment right away or make an appointment. Patients were included into the sample if they had received a clinical diagnosis of ADHD. Fourteen patients received their diagnoses before the age of 18 years. Twelve patients reported to have comorbid diagnoses. Thirty-three patients were treated with extended-release methylphenidate, two with Serotonin–Noradrenalin-Reuptake-Inhibitors and four were not taking medication. Patients were instructed to take their medication as usual and during the experiment 26 patients were under the influence of their medication . Twenty-four patients had received or were receiving psychotherapy.Demographic data of our sample is displayed in Table t-score above 65, t-scores have a mean of 50 and a standard deviation of 10) scores in two or three symptom scales of the CAARS inattention/memory problems, hyperactivity/restlessness and impulsivity/emotional lability. Two participants were excluded due to this criterion. The final control group included 39 control adults . Two participants reported to have received psychological diagnoses in the past (depression and adjustment disorder) and four reported psychotherapy. We compared the group with ADHD with the group without ADHD with regards to gender, age, country of birth, degree of education and did not find any significant group differences  as well as to take part in an IQ screening  and in the tests of attention . Finally, the last part of the session was the clinical interview (Wender-Reimherr-Interview [WRI]). After completion, participants received their reimbursement and were informed about the possibility to receive a written report about the results of the study in general. The session took approximately 2 h.The following table displays the results of the diagnostic measures. To avoid habituation or practice effects diagnostic measured used in this study differed from the diagnostic measures usually applied in the neurological outpatient practice where we recruited participants.The CAARS is a clinical questionnaire assessing attention problems in adults . We usednot present) to 2 (medium or high). The 28 items are part of seven subscales: inattention, hyperactivity, hot temper, mood instability, over reactivity, disorganization, impulsivity. The score is a sum of all items. Furthermore, there is a global rating for each scale judging symptom on a scale from 0 (not present) to 4 (severe). The WRI Global Score is a sum of the seven global ratings. Groups differed significantly in all scales and the global score of the WRI  . The WRIr being 0.847 for median reaction time, 0.885 for errors and 0.742 for omissions . The interaction between ADHD/control and task repetition/switch was not significant, F = 0.764, p < 0.385, ηp2 = 0.010. The three-way interaction between ADHD/control, task repetition/switch, and constant/mixed target levels was not significant, F = 2.262, p < 0.137, ηp2 = 0.029. More importantly however, these last two interactions were numerically consistent with the reaction times, i.e., longer reaction times correspond to higher error rates. Separate ANOVAs for the constant levels condition and the mixed levels condition revealed that the interaction between repetition/switch and ADHD/control was significant in the constant levels F = 4.325, p < 0.041, ηp2 = 0.055, but not in the mixed levels, F = 0.401, p < 0.528, ηp2 = 0.005. As can be seen in Fig. We also examined the aggregated average error rate for each participant and factor combination see Fig. . Again, F = 10.727, p < 0.001, ηp2 = 0.125. The only other significant effect was that the mixed target levels condition had more variable response times than the fixed one, F = 24.152, p < 0.001, ηp2 = 0.244. No significant interaction with ADHD/control was found.A typical result found in the literature on executive control is that patients with ADHD show more reaction time variability. Although many studies report results in the form of standard deviations, this may be misleading because slower responses have higher numerical values, and tend to result in higher standard deviations. We opted instead to compute standard deviations for each participant and factor combination, and divided these values by the corresponding averages to obtain coefficients of variability, thus controlling the effect of speed differences; we then analyzed these coefficients with ANOVA using the same factors as in the reaction time analyses. Comparing ADHD patients with controls, the first show a significantly higher variability in response times, A final important question in this study is whether TS and AtS shift are related in general to ADHD deficits. We calculated a crude measure of performance in these executive functions simply by subtracting for each participant the average reaction time in task repetitions from the average in task switches , and calculated this measure separately for the constant and mixed target levels halves of the experiment. Since these values are not corrected for age, sex or any other variable, we correlated these measurements with the raw values (no T-correction) of the scales attention, hyperactivity and impulsivity of the CAARS and WRI-HASE diagnostic tests. The results are displayed in Table TS cost in the constant target level condition correlated significantly with the CAARS Hyperactivity and Impulsivity scales, mixed level TS correlated significantly with the CAARS inattention and impulsivity scales, but only the TS cost in the mixed condition had a significant correlation with the WRI-HASE attention scale. The diagnostic scales correlated among themselves in a much stronger way  while the other half required shifting the AtS on each task switch. The stimuli never combined digits and letters. In light of the heterogeneity of findings obtained in task switching studies involving patients with ADHD , 38, 39,Identifying deficits in executive functioning constitutes a major challenge in clinical (neuro)psychology. It has been criticized, in this connection, that commonly used procedures are characterized by lack of theoretical justification and more specific assessment of separable components of executive functions are desirable , 41 ThisThe present study is consistent with the literature on ADHD showing more variable response times in TS experiments . Also, wHowever, patients did not display a larger difference in the size of the congruency effect in the mixed levels vs. the constant level condition than the control group. This result is reminiscent of previous findings of dissociations between overt responding to the global or local stimulus level and interference exerted by the other level e.g., , 46). Al. Al46]).A strength of the current study is the representativeness of the sample and the well-matched control group. We had about an equal number of male and female patients , 48. TheConcerning the relevance of our results for general ADHD symptoms, TS costs both in the constant and mixed target levels cases, correlated with the symptom scales of two ADHD diagnostic scales. Besides the unclear importance of TS without AtS shift, we deem our results robust enough to claim that attentional set shift is impaired in ADHD patients.


Bartonella, Coxiella, Rickettsia, Anaplasma and Ehrlichia, we conducted a descriptive epidemiological study in three biogeographic regions of the Brazilian Atlantic Forest.The role of bats as reservoirs of zoonotic agents, especially pathogenic bacteria such as Bartonella and Coxiella, has been discussed around the world. Recent studies have identified bats as potential hosts of species from the proteobacteria phylum. In Brazil, however, the role of bats in the natural cycle of these agents is poorly investigated and generally neglected. In order to analyze the participation of bats in the epidemiology of diseases caused by Bartonella spp. was detected in 22 spleen samples , whose phylogenetic analysis revealed the generation of at least two independent clusters, suggesting that these may be new unique genotypes of Bartonella species. In addition, four samples  were positive for the htpAB gene of C. burnetii . Rickettsia spp., Anaplasma and Ehrlichia were not identified. This is the first study reporting C. burnetii and Bartonella spp. infections in bats from the Atlantic Forest biome.Tissues of 119 bats captured in preserved areas in the states of Rio de Janeiro, Bahia and Santa Catarina from 2014 to 2015 were submitted to molecular analysis using specific primers. These findings shed light on potential host range for these bacteria, which are characterized as important zoonotic pathogens.The online version of this article (10.1186/s12917-018-1603-0) contains supplementary material, which is available to authorized users. Rickettsia, Bartonella, Coxiella, Ehrlichia and Anaplasma are pathogens of domestic and wild animals as well as humans. These agents cause diseases that may be severe and have a widespread geographic distribution, such as bartonelosis, ehrlichiosis, anaplasmosis, spotted fever, and Coxielosis/Q fever . A. ABartonBartonella species reported in the literature, which may indicate that previously unknown genotypes of Bartonella are infecting these bats. This is a common finding with studies of this agent in bats from other regions of the world  [Bartonella sequences found in wild rodents of the Atlantic Forest in the state of Rio de Janeiro (LBCE- Laboratory of Biology and Control of Schistosomiasis), reinforcing that a new genotype may be circulating among bats and that these strains differ between rodents and bats [S. lilium species were grouped into two distinct clades, suggesting that a single bat species is host to two different species of Bartonella. Similarly, sequences generated from Bahia, Rio de Janeiro and Santa Catarina states subjected to phylogenetic analyses were divided into two clades and suggested that the circulation of more than one species of Bartonella may be associated with bats in each state. Co-infection of different Bartonella species in a single bat species was also observed in Kenya, Guatemala, China and Georgia [Bartonella strains tend to cluster according to families, super-families and suborders of bats [Bartonella in a single species of bat may imply a change of bacteria via recombination, as shown by Bartonella in rodents [Bartonella lineage, since the divergence of the sampled sequences of the gltA gene varied from 0.0 to 20.9% in sequences of the same clade, the sequence divergence among Bartonella species suggested for this fragment is about 30% [Bartonella species, it is necessary to sequencing other housekeeping genes  to recognize the diversity of lineages found in bats and to determine the structure of populations and phylogenetic data [The phylogenetic tree revealed the formation of independent clades when compared to d China) , 27, 46.and bats . Interes Georgia . A recen of bats . In addi rodents . The prebout 30%  .The absence of n nature . Besideskettsial , 57. No mataceae , there iC. burnetii and Bartonella spp. in the Brazilian Atlantic Forest. To the best of our knowledge, this is the first study that reports C. burnetii infection in Brazilian bats and the first to report Bartonella spp. in the Atlantic Forest biome.This study confirms the presence of infected bats with Additional file 1:Bartonella gltA partial sequences. There were a total of 512 positions in the final dataset. Evolutionary analyses were conducted in MEGA7. Presentation of the PCR positive bats species for Bartonella spp. in this study with their respective GenBank accession numbers and the estimated divergence found between Bartonella gltA partial sequences of the gene deposited in GenBank. (DOCX 25 kb)Estimates of Evolutionary Divergence between


Using the ADHD-200 consortium, we characterized the time course of latent state changes using Hidden Markov Modeling, and compared state changes between boys and girls with ADHD along with typically developing controls. Sex differences were found in latent state switching, with boys dwelling longer in a given state than girls, and concurrently having fewer overall state transitions. These sex differences were found in children with ADHD and in typically developing controls. Children with ADHD were also found to be more variable in terms of state transitions than controls. These findings add to the growing literature on neural sex differences and may be related to the sex difference in focal versus diffuse attention.Neuroimaging studies of subjects with ADHD typically show altered functional connectivity in prefrontal, striatal, and several temporal brain regions. While the majority of studies have focused on connectivity that is averaged over time, we investigated the temporal dynamics of brain network changes in resting-state  Attention-Deficit/Hyperactivity Disorder (ADHD) affects at least 5% of children and adolescents –4. Its pThere are two- to three boys for every girl diagnosed with ADHD , as wellHere, we first review the neuroimaging literature on both ADHD and sex differences, , andNeurological deficits have long been thought to contribute to ADHD , and theIn typically developing children, temporal coherence generally increases with age, and the relatively poor temporal coherence in children with ADHD might reflect a developmental delay. Either way, decreased temporal coherence between the DMN and other cortical regions is often found for children with ADHD –28. IndeMoreover, children with ADHD often differ from other children in terms of functional connectivity involving regions of the prefrontal cortex. In a resting-state study, Bos et al. found increased but more diffuse connectivity patterns in the medial PFC and the inferior frontal gyrus in children with ADHD relative to typically developing children . Other sThese neuroimaging findings are consistent with differences in multiple brain networks of children with ADHD relative to their typically developing peers. Differences in the DMN suggest that children with ADHD may not engage in the same forms of mind wandering as typically developing children, and differences in the frontal-striatal, frontoparietal control, and attention  networks are consistent with deficits in executive functioning and cognitive control. The relation between the DMN and attentional networks is also important: specifically, for shifting from self-referential cognition associated with episodic memory to the attentional focus needed to address specific, non-self-referential demands . In othed = .9) on a composite measure of diffuse versus focused attention, after controlling for general intelligence [It is currently unclear whether the sex difference in the prevalence of ADHD is an exaggeration of more general sex differences in verbal, motor, or brain function or reflects something unique to ADHD. Generally, many sex differences are similar to those found in ADHD. For instance, sex differences have been found in functional connectivity within both the DMN and the sensorimotor cortices –45. Aparlligence . Men on fMRI, as is commonly done in static functional connectivity analyses. Given sex differences in ADHD symptomatology, the over-representation of males among individuals with ADHD, and the sex difference in focused-diffuse attention, the study of sex and diagnostic differences in temporal dynamics of state, or network, changes in resting-state fMRI could provide unique insights into ADHD and sex differences linked to ADHD more specifically. Here, we use computational modeling to estimate latent, or hidden, brain states and to quantify whole-brain changes in state dynamics as a function of ADHD diagnosis and sex.Although many potentially important ADHD-related and sex differences in brain structure and functions have been identified, relatively little is known about the temporal dynamic changes of brain activity in these individuals. In one study, Alba et al. observed no significant group differences in averaged connectivity between subjects with ADHD and controls, although ADHD subjects showed more variability in connectivity over time in frontal and parieto-occipital regions relative to controls . HoweverSubject characteristics including sample size, age, and basis for ADHD diagnosis can be found in Latent states from the rs-fMRI time series data were estimated using Hidden Markov Modeling (HMM) for each group separately. To resolve potential differences in the nature of each state for the four groups , and to combine similar states across the groups, k-means clustering was performed. A five-cluster model was chosen, using the mean activation maps for each of the 20 estimated states (i.e. five states for each of the four groups). Results from the cluster analysis showed that each cluster appropriately contained only one mean activation map from each experimental group (sex × diagnosis). In other words, the HMM identified five states that were similar across the four groups. Thus, mean activation maps were calculated for each of the five states by averaging maps across all four groups. These were then transformed into brain space and are plotted in F = 666.32, p < .001, ηp2 = .52. In particular, typically developing boys and girls had the highest fractional occupancy in the fourth latent state, whereas fractional occupancy for girls and boys with ADHD was the highest in states five and three, respectively. Transition probability matrices (TPMs) were estimated for each group to detail the probability of switching from one particular state to another. As is apparent in M = .53, SD = .04) compared to switching to other specific states . Apart from a higher tendency to remain in the same state as the preceding time point, transition probabilities appear to be nonspecific, such that there are similar probabilities for switches across states . While there are subtle asymmetries in transition directionality , no consistent pattern is evident that would explain overall differences between sex or diagnosis. State switching differences are thus more prevalent in terms of their general duration and frequency.Next, fractional occupancy was calculated separately for each group, which provided the overall proportion of time each state was visited throughout the time series. These estimates averaged across subjects can be found in M = 1.17, SD = 0.33) dwelled longer on average than girls  in any given state, F = 8.63, p = .003, ηp2 = .01. There were no differences for mean ITI estimates across diagnostic category; children with ADHD , control children , F < 0.01, p = .95, ηp2 < .001. Additionally, there was no interaction between sex and diagnostic category, F = 0.02, p = .90, ηp2 < .001.p > .05). This pattern of longer dwelling times was primarily driven by states two, three, and four . These relate to networks similar to the VAN, DMN, and SMN, respectively.To further explore which states were driving sex differences, ITI’s for each individual state were similarly calculated as the average number of consecutive time points in each state before a switch to a new state. As can be seen in the left side of M = 1.70, SD = 0.55) than control children , F = 4.69, p = .03, ηp2 = .005. There was slightly greater variability in ITI among boys  than girls  in state switching, albeit the difference was not statistically significant, F = 3.32, p = .07, ηp2 = .004. The interaction between sex and diagnosis was also not significant, F = 0.001, p = .98, ηp2 < .001. Analogous to ITI means, to further explore which individual states were driving diagnosis differences in ITI variability, state-specific estimates were calculated. As can be seen on the right side of p = .002, d = 0.28).The standard deviation of ITI was used as an indicator of variability. Children with ADHD were more variable as a group  had more NTs than boys , F = 11.25, p = .001, ηp2 = .01. This result is consistent with the numerical sex difference in ITI, which was to be expected, as the ITI and NT measures are highly correlated . Neither the main effect of diagnosis, F = 0.06, p = .80, nor the interaction between diagnosis and sex, F = 0.18, p = .67, were significant.The number of transitions (NTs) indexes the frequency of state changes across the time series, divided by the overall length of the time series for each subject. Data were again screened for outliers, and eight runs were identified and removed from the analysis. There is now ample evidence for structural and functional connectivity differences across the sexes and for children with ADHD relative to their typically developing peers. Studies have shown functional connectivity differences, where women exhibited more coherent connectivity in regions overlapping with the DMN, and men generally having stronger connectivity in sensorimotor areas . In a sifMRI. While HMM characterizes data as a series of latent states, the use of HMMs assume that the system under scrutiny is in one state at any given point in time . While the inferred state at time t is the reflection of the highest probability over other potential states, it could be the case that two states at time t have relatively similar probabilities. Thus, there can be some uncertainty in the model at equivocal time points as to which states are truly reflected in neural data.Neuroimaging studies of children with ADHD show structural and functional differences compared to their typically-developing peers. Atypical functional connectivity in ADHD has been identified in prefrontal, striatal, cerebellar, and temporal regions, along with regions commonly found in the DMN –24. The Our results contribute to this growing body of research on sex differences in the brain. Along with differences in static functional connectivity , we reveWe cannot be certain because Johnson and Bouchard  assessedIn any case, sex differences in attentional focus might result from slow switching to or from attention networks to frontoparietal control and/or DMN networks. Dwelling in the DAN or VAN would facilitate performance in attention-demanding tasks, whereas dwelling in another state and delaying the switch to attention networks would hamper performance. One result would be greater variability among males. State switching deficits might also contribute to some of the impulsivity and executive function symptoms commonly seen in boys with ADHD. However, many of the control boys showed the same pattern and thus ITI and NT did not interact with diagnosis. Again, the resting-state condition, with few if any external distractors, might have obscured any underlying differences.No sex differences were observed in the variability of state switching. However, children (both boys and girls) with ADHD were found to be more variable in state switching than were typically developing controls. The children with ADHD also tended to dwell in different states than typically developing children. The functional significance of dwelling in one state or another cannot be determined at this time, but suggests that even during rest the patterns of global brain activity and change in the distribution of this activity differ in children with ADHD relative to typically developing children. This result adds to the vast literature detailing aberrant static functional connectivity in ADHD. Along with general connectivity strength differences, we found that typical dynamic state switching may be altered in children with ADHD, showing greater variability than controls that in turn might be specific to regions within the DMN. Furthering research in areas related to the classification of various neurological and psychiatric disorders should begin to address the degree of non-stationarity in neural signals that may be dissociable at the individual level. By using dynamic modeling approaches such as HMM, we can begin to study the structure of intraindividual variation in cases where latent categorical processes may be present . Many neF = 9.09, p = .003, ηp2 = .02, as well as the main effect of diagnosis in ITI variability estimates, F = 6.79, p = .01, ηp2 = .02. For NT, the main effect of sex also remained unchanged, F = 4.31, p = .04, ηp2 = .01. More details as well as visualizations from the sub-sample analysis can be found in the supplementary materials. Another important consideration is that whereas concatenating data from multiple individuals  may not fully reveal individual-specific dynamic changes, analysis based on intraindividual variation seems like an appealing future direction.Further research that continually utilizes larger samples will be beneficial. The sample in the current analysis was asymmetric . However, in a sub-sample analysis, where subjects were randomly sampled from the other three groups to match the size of the smallest group, results remained unchanged. For ITI, the main effect of sex was still present, fMRI, experiments using task-based paradigms can also show dynamic changes in response to various stimuli (i.e. attention tasks). The current study elucidated sex and ADHD differences in neural state switching, and while we may hypothesize how this might relate to behavioral deficits between males and females with and without ADHD, directly relating this to behavioral performance in future research seems crucial. Overall, we found that resting-state fMRI carries dynamic information pertaining to subject sex and ADHD diagnosis.Developmental studies tracking changes in behavior and neural function across the lifespan may also elucidate dynamic shifts in activity as a function of time. Along with resting-state http://fcon_1000.projects.nitrc.org/indi/adhd200/) were selected for the current study, as shown in Data from subjects recruited for the ADHD-200 consortium , repetition time , and voxel size (3-3.8 mm in-plane resolution and 3-4 mm slice thickness).Across the multiple sites, different models of scanners  and scanning parameters were employed. See  for fullhttp://www.arc.vt.edu). The preprocessing pipeline, also known as the ‘Athena processing pipeline’, was based on a combination of functions from the AFNI [Publicly available versions of the pre-processed imaging data were used for the current study . Preprocthe AFNI  and FSL the AFNI  toolboxethe AFNI , resamplthe AFNI , 57 and the AFNI , 58.https://osf.io/xqewf/. Analysis of the rs-fMRI data first employed Bayesian Hidden Markov Modelling (HMM). The method was recently adapted for use with rs-fMRI to assess how network-related activity exhibits stability versus change across time [Data analysis was performed using Python v. 3.6.4 and R v. 3.5.0. Code and supplementary materials can be found online at oss time –60. In-doss time , 61–63. oss time , as thesoss time , 65). WhOur analysis of HMM parameter estimates was based on the work from Hutchison and Morton . A modeltransition probability matrices (TPMs) were extracted from the model, which for each group details the probability of switching from one particular state to another. Third, fractional occupancy (FO) which is the proportion of all time points (TRs) that correspond to a particular state, and which indicates the states that were most prevalent across subjects, was calculated and inspected for each group. A note to consider is that FO values might be minimally influenced by inter-group differences in mean activation maps for various states. While the majority of variance agrees across groups for each state, there are subtle differences in the spatial extent between groups. Thus, differences between groups in FO values might be partly attributable to these differences. However, in the absence of any clear pattern distinguishing between sex or ADHD diagnosis, differences in FO values should be interpreted with caution.After the final HMM was estimated for each group, the latent state properties for each group were inspected in three ways. First, mean activation maps for each latent state were extracted and plotted as whole-brain maps. Second, Inter-transition interval (ITI) is the number of consecutive time points that subjects dwell in any one state before switching to another, and was averaged across all states for each individual subject. Finally, the number of transitions (NT) was calculated as the number of times a change between any two states was detected. This measure was averaged across the number of time points in each individual time series and thus indicates the frequency of state switching. Using these measures, the primary analyses focused on changes in mean and standard deviation estimates for the inter-transition interval, as well as the average number of transitions across the four groups of subjects .Additionally, two critical measures were used in analyses to estimate state change dynamics.


Emotional lability is a common problem in adult patients with ADHD and is usually treated with methylphenidate. It is generally known that music can be used to improve mood in healthy adults. Therefore, this study was conducted to test the suitability of music as a possible non-pharmacological measure to improve mood. Forty patients with ADHD and 44 healthy control subjects were randomly assigned to one of two experimental conditions. The first group (music group) listened to Mozart’s music (KV 448) for 10 min while the second group remained in a silent room for 10 min (silence group). Subjective arousal and mood were assessed using self-report questionnaires before and after each condition. We showed that music listening led to a decrease in negative mood (sadness and hopelessness) in the ADHD group as well as in healthy controls. This effect was not evident in both silence groups. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests during childhood. Even though ADHD is a childhood disorder approximately 60% of the cases show persistence of symptoms into adulthood . ADHD isAn important aspect underlying emotional regulation is the ability to regulate arousal levels. A theory for ADHD that gives arousal regulation a central role is the Optimal Stimulation Theory (OST), firstly described by It has been clearly demonstrated that music, especially the music of Mozart increases subjects’ arousal levels by increasing the sympathetic tone . In addiN = 10 subjects. In contrast, the healthy control group consisted of 44 subjects. In the group of healthy controls, gender frequencies and distribution were equal to the ADHD group with the exception of the experimental condition consisting of 14 female and 10 male subjects. There were no significant gender differences in any of the examined measures, all p > 0.05. Mean age in the ADHD group was 33 years (SD = 9.6) and 28.4 years (SD = 12.3) in the healthy control group, respectively. Participants were randomly assigned to each experimental condition (music vs. silence).We conducted a 2 × 2 factorial design. The two defined factors were diagnosis  and condition (music vs. silence). Overall, 92 subjects participated in the study. However, due to missing data and apparent failures to comply with all instructions four subjects had to be excluded from data analyses, therefore yielding a total of 84 study subjects. The ADHD group consisted of 40 subjects, equally distributed between male and female subjects in each experimental (music listening) and control (silence) condition. Each subgroup consisted of All patients were diagnosed with ADHD according to the DSM-IV and ICD-10 criteria by consultant psychiatrists and psychologists. Concerning subtypes the ADHD group consisted of the mixed subtype entirely. According to the DSM-IV  the mixeQuestionnaires assessing current difficulties related to attention, hyperactivity and impulsivity  , baselinInclusion criteria for the patient group were a confirmed diagnosis of ADHD. Subjects with a history of substance abuse or psychotic disorder, a prevalent and confirmed personality disorder or disorders of the autism spectrum as well as any neurological diseases, asthma, obesity or diabetes or hearing problems were excluded from participation.The study was assessed and approved by the Ethics Committee of the Faculty of Medicine of the University of Duisburg-Essen and was conducted in accordance with the Helsinki Declaration.®(version 2.1.0) to yield a total length of exactly 10 min by simply repeating the music from the beginning until 10 min had passed in order to ensure comparability to previously conducted studies . This piece of music with an original length of 8 min and 24 s was edited using Audacity studies . Music wTo measure subjective arousal levels and mood we used the Current Mood Scale [‘Aktuelle Stimmungsskala’ (ASTS), In addition, the participants’ subjective arousal levels were measured with a German version based on the Global Mood-Arousal Scale (GMAS) by To ensure that subjects did not differ in musical proficiency between groups we assessed subjects’ previous experience with musical training .To assess subjects’ familiarity and preference with the music used in the study, subjects were told to answer five short questions that were answered using a seven-point Likert scale . Questions such as: “Did you like the music you just heard?” or “How familiar was this music piece to you?” This music-questionnaire was filled out by participants in the music-condition and was completed in less than 2 min. The questionnaire was applied to ensure that subjects’ familiarity and preferences did not differ significantly between subjects. Participants in the silence condition waited an additional 2 min with the experimenter back in the room.Following the administration of the above-mentioned clinical self-report questionnaires and the MWT-B, the experiment was implemented in the following manner: participants were given the Current Mood Scale (ASTS) and the GMAS (T0). Hereafter, subjects listened to music (KV 448) for 10 min in a room by themselves (music condition) or sat in a room by themselves and doing nothing for 10 min (silence condition). During that time the experimenter was not in the room. Subjects were instructed to simply listen to the music and in the case of the silence-condition subjects were instructed to do nothing and simply remain seated until the experimenter would reenter the room after 10 min. After the 10 min had passed, the experimenter would reenter the room, administered the short music-questionnaire in the music condition or waited an additional 2 min with the subjects in the silence group and then asked the participants to fill out the ASTS and GMAS (T1) again.U test and the Wilcoxon test. Effects of listening to music and waiting in silence on fatigue and current mood were examined using the Wilcoxon signed-rank test. Examination of possible interaction effects between groups  and the effects of music listening on current mood and arousal in a pre–post comparison was calculated using the Mann–Whitney U test. The following subscales of the ASTS were used for statistical analyses: hopelessness, sadness, fatigue, anger as well as negative mood and positive mood.We conducted a 2 × 2 factorial design. The two defined factors were diagnosis  and condition (music vs. silence). Statistical analyses were performed using SPSS (IBM Version 23). Mathematical prerequisites of the General Linear Model like for example normal distribution assumptions were not met (measures ASTS and GMAS). Normal distribution was tested using the Kolmogorov–Smirnov test. We therefore used non-parametric tests such as the Mann–Whitney p < 0.05.Accordingly, correlations were calculated using Pearson’s Product-Moment-correlations and Spearman-Rho rank correlations. Alpha was set at Sad = -2.41, p = 0.016  as well as UHopeless = -2.26, p = 0.024 . Both results show moderate effects of d = 0.22 for USad and d = 0.29 for UHopeless. We decided to calculate all Cohen’s d with the larger standard deviation of both groups to achieve a more conservative result. There were no significant differences in all other subscales of the Current Mood Scale (ASTS), such as fatigue, as well as in subjective measures of arousal (GMAS), all p > 0.05.Listening to music significantly reduced the state of sadness and hopelessness in patients with ADHD with UFatigue = -3.13, p = 0.002 , and decreased negative mood with UNeg.Mood = -3.09, p = 0.002 . In addition, the subscales sadness  and hopelessness  were also affected by the music in the healthy control group. As in the group of ADHD patients, we observed moderate effect sizes in the healthy control group as well.In healthy controls listening to music decreased subjectively perceived fatigue with UIn patients with ADHD, the effects of remaining in a silent room for 10 min yielded mixed results. We found significant worsening of current mood and an increase of arousal.Pos.Mood = -2.92, p = 0.004  whereas the total score for negative mood increased significantly with UNeg.Mood = -2.36, p = 0.018 .Specifically the total score for positive mood decreased significantly with UGMAS = -2.00, p = 0.046 .Arousal was also significantly increased due to waiting in silence in patients with ADHD, Up > 0.05. p > 0.05.In healthy controls, there were neither significant changes in any of the subscales of the Current Mood Scale (ASTS) nor any significant changes for the GMAS in the silence condition, all p > 0.171. Regarding specifically those results concerning the subscales sadness and hopelessness in the group of patients with ADHD in which music improved current mood, descriptive analyses yielded the following results. In the group of patients with ADHD listening to music the absolute mean magnitude of change for the subscale sadness equals M = 0.63 (SD = 1.01), p = 0.266, for the subscale hopelessness the absolute mean magnitude of change equals M = 0.58 (SD = 1.22), p = 0.798.Examining the magnitude of change for current mood subscales sadness, hopelessness, fatigue, positive mood, and negative mood before and after listening to music, we did not detect any significant differences between healthy controls and patients with ADHD, all +) and those that did not listen to music , with MMusic+ = 14.00; SD = 11.68 and MMusic- = 18.89; SD = 12.19, p = 0.317.BDI scores did not significantly differ between the group of patients with ADHD that listened to music  and the group of healthy controls had a mean of M = 5.21 (SD = 1.38), p = 0.232. Even more, there was no difference between familiarity with the musical piece used for the study. Using a seven-point Likert scale asking whether subjects were familiar with the music heard, healthy controls had a mean of M = 2.83 (SD = 1.99) and the group of patients with ADHD had a mean of M = 2.95 (SD = 1.96), p = 0.788.Concerning the music piece used for the present study, there were no significant differences regarding familiarity and liking between the patients with ADHD und the healthy controls that listened to the music, all p = 0.07. Among the group of healthy controls that listened to the music 11 subjects had played an instrument whereas 12 subjects did not, p = 0.835. In general, comparing healthy controls and patients with ADHD regardless of any experimental condition (music or silence) there was no significant difference between the two groups concerning the number of subjects playing or having played an instrument, p = 0.086.Regarding musical training, there were no significant differences between any groups of interest. Among the group of patients with ADHD that listened to the music six patients played an instrument or had played an instrument in the past and 14 patients did not play any instruments, To our knowledge, this is the first study to investigate the effects of music on mood and subjective arousal levels in adult patients with ADHD using Mozart’s music (KV 448). Listening to Mozart’s music improved current mood scores (sadness and hopelessness) in adult patients with ADHD. In addition, those findings extended to healthy controls. Hereby, current mood scores for sadness and hopelessness as well as current mood scores for subjectively perceived fatigue were improved.In contrast, patients with ADHD waiting in silence for 10 min exhibited a significant increase in arousal and negative mood and a decrease in positive mood.To our knowledge this is the first study to demonstrate the negative effects of waiting in silence while being restrained from any activity on mood and arousal in a sample of adult patients with ADHD. According to the OST  a restraBefore implementing the above-mentioned results into non-pharmacological treatment plans for this specific group of patients further studies are needed to replicate those findings using lager sample sizes to thereby increase power and also to control for limitations mentioned below.The following methodological limitations should be considered when interpreting these data. First, it cannot be entirely ruled out that the significantly higher BDI scores for depressed mood in the ADHD group had an impact on how arousal and positive mood were able to be altered by listening to music. However, there was no significant difference in baseline BDI scores between the music and the silence group among patients with ADHD. Therefore, music as compared to silence seems to differentially effect current mood, specifically sadness and hopelessness.Furthermore, it remains possible that patients with ADHD were more prone to rumination during the silence condition due to higher BDI scores, which then increased negative mood and subjectively perceived arousal in the ADHD group. Further studies need to elucidate the effects of increased measures of a heightened self-report measure of depressive symptoms on arousal and mood. Nevertheless, we emphasize that the diagnosis of a clinically relevant Major Depression was ruled out in all participating subjects. Even more, increased scores for negative mood in the patient group might also be due to boredom that this patient group is especially prone to.Second, due to the fact that the experimenter was not in the same room during the music or the silence condition, it remains unclear whether all participants complied with the request to remain calm and quiet and to do absolutely nothing during the 10-min waiting in silence condition or the music condition. However, we clearly reject the alternative – the experimenter being in the same room with the participants. It would have been possible for the participants to talk to the experimenter thus interfering with the listening task or the silence-condition. Furthermore, subjects could have simply been distracted or even agitated by the possible presence of the experimenter. Nevertheless, the negative effects on mood and arousal mentioned above give a hint of compliance in the ADHD group.We also rejected the possibility of using videorecording to control for adherence to task instructions. Here again, we see the same arguments apply that were just mentioned. Apart from any ethical considerations, we do not fully know possible negative effects of using videorecording on patients’ mood.Third, the interpretation of the results is limited by the fact that only self-report questionnaires were used to measure arousal levels and changes in mood state. We have not used objective physiological measures such as EEG or ECG as for example This study was carried out in accordance with the recommendations of the Ethics Committee of the Faculty of Medicine of the University of Duisburg-Essen. The protocol was approved by the Ethics Committee of the Faculty of Medicine of the University of Duisburg-Essen. All subjects gave written informed consent in accordance with the Declaration of Helsinki.MZ conceived and designed the experiments. MZ and LS performed the experiments. MZ, KD, LS, and CM analyzed the data. NS and CM contributed to the reagents, materials, and analysis tools. MZ, KD, LS, NS, and CM wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AC and handling Editor declared their shared affiliation at the time of review.


N = 1258).While the keeping of pets has been shown to protect against childhood allergic disease and obesity, less is known regarding potential associations of prenatal pet keeping and attention deficit hyperactivity disorder (ADHD). We sought to examine the associations between prenatal dog or cat keeping with caregiver-reported ADHD in preadolescents in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort  was ascertained. Logistic regression models were fit to examine the association of prenatal pet keeping  with ADHD.p = 0.017) greater odds of ADHD among boys. Prenatal dog keeping was not statistically significantly associated with ADHD in girls . Prenatal cat keeping was not associated with ADHD.A subset of 627 children were included in the analyses: 93 who had ADHD and 534 with neurotypical development. After accounting for confounders and loss to follow-up, maternal prenatal dog exposure was associated with 2.23 times  is needed. The keeping of pets has been shown to have a variety of both positive and negative health effects –8. ChildPets may influence neurodevelopment via several pathways. Pets are associated with changes in the gut microbiome of members of their household , 18. TheADHD is a complex disorder hallmarked by hyperactivity, inattention and impulsivity at a developmentally inappropriate level . In the The goal of this study was to examine if prenatal pet keeping was associated with ADHD in preadolescence (ages ~ 10–12 years). To achieve this goal, we leveraged data from the racially and socioeconomically diverse Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort  , 33, 34.WHEALS recruited pregnant women with due dates from September 2003 through December 2007, and who were seeing a practitioner at 1 of 5 clinics in the Henry Ford Health System to establish a birth cohort , 34. AllAt the age 10–12 year visit, the caregiver (95% the mother) reported if the child had ever been diagnosed with ADHD. The caregiver also reported if the child had ever been diagnosed with autism spectrum disorder (ASD), Asperger’s syndrome, or sensory processing disorder (SPD); Asperger’s syndrome was asked separately since children may have been diagnosed prior to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). A report of “suspect” diagnosis was also considered positive. Children were considered neurotypical (NT) if they did not have a caregiver-reported ASD, Asperger’s, ADHD, or SPD diagnosis. Children without an ADHD diagnosis but who had a caregiver-reported ASD, Asperger’s or SPD diagnosis were excluded from the analysis, given the small sample size with these conditions.A subset of 325 WHEALS children had their medical record abstracted for additional health information, including ADHD diagnosis. Caregiver report of ADHD diagnosis was validated within this subset using the kappa (κ) statistic to evaluate agreement. Landis and Koch  criteriaDuring the prenatal maternal interview, the mother was asked about presence of pets in the home, the number of hours they spent indoors, and the type of pet . Some studies have attributed health benefits primarily to dog ownership , 36, 37;The mother self-reported race, date of birth, marital status, household income, education, parity, smoking history and exposure to environmental tobacco smoke at the prenatal interview. Maternal prenatal care records were abstracted to obtain antibiotic and antifungal use . Height Differences in basic characteristics by ADHD vs. NT development were first compared using standard parametric statistical methods, including chi-square tests and analysis of variance. Prenatal pet exposure  was then associated with ADHD using logistic regression to obtain odds ratios (OR) and 95% CIs. Given the growing and consistent evidence that male fetuses are more vulnerable than female fetuses to exposures during gestation , sex-speNot all WHEALS children/caregiver pairs completed a 10–12 year questionnaire  and outcome (ADHD) were used to calculate 25 total imputed datasets. Each imputed dataset was modeled using logistic regression ; final effect estimates were obtained by pooling results. All analyses were performed using SAS version 9.4  and R version 3.4.1.n = 6), SPD (n = 7), or both (n = 3) without an ADHD diagnosis were excluded. Therefore, our final analytic sample consisted of 627 children: 93 with an ADHD diagnosis and 534 NT children. Differences in those who did and did not complete the 10–12 year questionnaire data are presented in Table p < 0.05). Additionally, they were less likely to smoke prenatally and be exposed to environmental tobacco smoke prenatally; the children of these mothers were also heavier at birth and were more likely to complete the 2-year clinic visit . However, though the standardized differences (D) of these effects were often large, inverse probability weighting adequately removed these imbalances . Children with ADHD were more likely to have mothers that used antifungals prenatally (p = 0.004) and who had a higher BMI recorded at the first prenatal visit (p = 0.002). Additionally, children with ADHD had an earlier mean gestational age at delivery  and were more likely to have been born preterm than NT children (p = 0.018).Table p = 0.308). There was no statistically significant difference in prenatal exposure to cats in children with ADHD compared to NT children .In unadjusted and unweighted analyses, children with ADHD were more likely to have had a mother exposed to dogs prenatally (30.1%) compared to children with NT development (25.1%), although this was not statistically significant (p = 0.124), though the direction of association was the same .After adjustment for loss to follow-up using IPW, the association between prenatal exposure to dogs and ADHD remained nonsignificant (p = 0.007). Specifically, maternal prenatal exposure to dogs was statistically significantly associated with increased odds of ADHD among males , but not females . Conversely, the effect of cats on ADHD was not significantly modified by sex  or by introduction of outdoor pesticides or toxicants into the home. For example, in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, a population-based study of children in California with ASD, developmental delays, and children from the general population, children with ASD had higher odds of having prenatal exposure to the flea and tick medication imidacloprid . Pet dogOur study has a number of strengths and limitations. The prevalence of ADHD in WHEALS is comparable to the prevalence of ADHD reported in Michigan in 2011 (14.5% versus 12.8%) . It is uIn conclusion, we found evidence that maternal exposure to dogs prenatally is positively associated with caregiver-reported ADHD in boys at ages 10–12 years. Future studies that replicate these findings are needed, as are studies that evaluate potential mechanisms linking these factors .


Connectivity continues to become more negative between these networks throughout development (7–15 years of age) in children with ADHD (p = 0.005). Regardless of group status, females had increased negative connectivity (p = 0.003). In regards to attentional performance, the ADHD group had poorer signal detection (d′) on the continuous performance task (CPT) (p < 0.0001), more so on easy than difficult d′ trials (p < 0.0001). The reduced negative connectivity in children with ADHD also relates to their attention, where increased negative connectivity is related to better performance on the d′ measure of the CPT (p = 0.008). These results highlight and further strengthen prior reports underscoring the role of segregated system integrity in ADHD.In children with attention deficit hyperactivity disorder (ADHD) difficulty maintaining task focus may relate to the coordinated, negatively correlated activity between brain networks that support the initiation and maintenance of task sets (task positive networks) and networks that mediate internally directed processes . Here, resting-state functional connectivity MRI between these networks was examined in ADHD, across development, and in relation to attention. Children with ADHD had reduced negative connectivity between task positive and task negative networks ( Maintaining task focus has been thought to relate to the coordinated activity between brain networks that support the initiation and maintenance of task sets (task positive networks) and networks that mediate internally directed processes . Here we find that segregation between these functional networks is impaired in children with ADHD, shows developmental lag, and is related to attentional impairments as measured by the continuous performance task. These results highlight and further strengthen prior reports underscoring the role of segregated system integrity in ADHD and its relationship to impairments in attention. Attention deficit hyperactivity disorder (ADHD) is a major public health concern that affects an estimated 5% of children in the United States , and connections that show age-related effects also show larger ADHD group differences , but it is also possible to manipulate the discrimination difficulty by including stimuli that are either more or less distinct from each other  and included 89 males. The average age of the ADHD group was 11.05 (SD = 1.58) and consisted of 181 males. Sex and age were included as covariates and follow-up analyses matched the number of male and female scans included in each group. See the Supplementary Information  and were included in the final analysis. The control group consisted of 176 children with a total of 231 total scans; 51 subjects had two scans and two subjects had three scans. The ADHD group had 256 subjects, 373 total scans; 85 subjects had two scans and 15 subjects had three scans. Children were between 7 and 11 years at baseline, and the lag design of approximately one year spans 7–15 years . The average age of the control group was 10.67 years (https://db.humanconnectome.org).An independent dataset was used in order to define the connections that are most anticorrelated between the task positive and task negative networks. For this analysis we used data from the Human Connectome Project (HCP) consortium “500 Subject” release and included 61 healthy adult control subjects , which were selected based on their optimal data quality and low motion  was used to examine vigilance and sustained attention . For data analysis, we selected 333 regions of interest (ROIs) with predefined network affiliation based on prior work . See Not all connections between task positive and task negative networks confer negative correlations . If interaction terms are insignificant, only main effects will be modeled for subsequent analyses, unless otherwise stated. Statistics were computed using a linear mixed-effects model . Individual parameter effects were estimated with the R package, lmerTest. Linear mixed effects modeling allows for an estimation of the fixed effects while incorporating the longitudinal nature of the data by including within-subject variation as nested random effects.The R package MuMIn was used to evaluate the best fitting model and Akaike information criterion (AIC) was evaluated for model selection and to guard against overfitting. Statistical effects were evaluated with three models; Model 1 considered only main effects, Model 2 included a group by age interaction, and Model 3 was a full omnibus model including a three-way interaction between age, group, and sex  for each connection were summed for each parameter effect of interest in a given direction . This summed t score for each region then visualized on the cortical surface. This analysis depicts a region’s influence on each effect of interest.Connection-level analyses separately modeled each of the 250 connections between networks and identified connections that were significantly .In order to ensure our results were not driven by an imbalance in gender distribution between groups , we performed confirmatory analyses that matched the gender distribution between groups. For these analyses 123 ADHD male scans and 100 ADHD female scans were randomly selected  in order to match the control distribution. Statistical models were refit with this matched subset and parameter effects were recomputed. This process was repeated 10,000 times, each time randomly selecting a subset of ADHD subjects, and the distribution of R < −0.35 (corresponding to the 5% strongest negative connections) were included in the network mask used for the main analyses. To ensure these effects were not threshold dependent, supplementary analyses tested anticorrelated network masks of R < −0.3 and R < −0.375  and task positive networks that were most highly anticorrelated. Connections that survived a threshold of df = 7, AIC = −1,011) followed by Model 2, which included all two-way interactions, , followed by Model 3 which also included a three-way interaction between group, age, and sex .A major aim of this study was to examine whether negative connectivity between task positive and task negative networks is distinct in children with ADHD, between sexes, and whether these connectivity patterns continue to mature across development. See Supplementary Table 3  and sex (p = 0.044) effects remained significant. This suggests that these differences in connectivity are not purely due to vigilance deficits, but are also related to other aspects of ADHD and sex.We found that ADHD subjects had reduced negative connectivity than control subjects. This was consistent across all three statistical models  are visualized in p < 0.05 is listed in Supplementary Table 4 . We found no group by sex interaction . However, we also found a trend towards an age by group interaction , where children with ADHD showed a stronger age by connectivity relationship  than controls . This suggests that the effect of age may be driven by children with ADHD . Results are also robust to connection density of the network mask , group status (p = 0.0081) and gender (p = 0.0083) remained significantly related to negative connectivity. After balancing the distribution of genders between groups, the main effect of age is no longer evident across groups (p = 0.187), but may be driven by a trend-level effect in ADHD subjects .Finally, in order to address the gender imbalance in our sample , a permutation approach was taken to randomly select subjects from the ADHD group to match the gender distribution in the control sample. p < 0.05 (FDR corrected) using Model 1. Of note is that an abundance of connections influencing the group and age effects are found between the default mode and dorsal attention and cingulo-opercular networks, and that only connections between default and the cingulo-opercular drive gender effects.Each of the analyses above focused on main effects on an averaged metric of negative connectivity between task positive and task negative networks. In order to examine the particular connections driving this effect, we next assessed the individual connections driving group, sex, and age effects. A list of connections between these networks (250-connection network mask), which showed significant main effects of group, age, and sex, are listed in Supplementary Table 4 . We also found that performance on the CPT improved with age (p < 0.0001). Importantly, we found a group by task difficulty interaction (interaction effect controlling for age and sex (p < 0.0001), where ADHD children had worse performance than controls on easy discrimination trials  than on difficult trails . Although children with ADHD were impaired on both easy and difficult discriminations, the larger difference on easy trials suggests that children with ADHD have more attentional difficulties when task demands are low. No other interactions were significant, and gender was unrelated to performance on the CPT (p = 0.61).As expected, we found that children with ADHD had worse performance on the d′ measure of the CPT, an index assessing attentional vigilance . This relationship was similar for easy and difficult trials , suggesting that connectivity was related to both difficult  and easy  d′ measures . This relationship was not moderated by age or sex. However, a trend was observed where ADHD subjects showed a stronger relationship between average connectivity and the d′ (easy) than controls (group by behavior interaction p = 0.072). Post hoc analyses in the control group show no relationship between connectivity and d′ easy (p = 0.603) but do show a significant relationship when only analyzing ADHD subjects (p = 0.033). Difficult d′ conditions are trend level in the ADHD group (p = 0.103) and nonsignificant in control subjects (p = 0.342). Taken together this suggests that the relationship between easy discriminability trials on the CPT and average connectivity is driven by subjects with ADHD. These findings were also unrelated to motion (see p = 0.045) but not difficult trials (p = 0.13). In the gender-balanced analysis, the CPT-connectivity relationship was only somewhat moderated by group status (p = 0.11), potentially because of a decrease in statistical power.In a repeated measures analyses including all subjects and both d′ measures of task difficulty , more negative connectivity was related to better attentional performance . These findings might suggest a few things. The first is that in typical children, this system is developed by early childhood and will not continue to mature into the early teen years. While there are several pieces of literature that would suggest the continued maturation of this system , MH096773 (Fair), MH099064 (Nigg), and MH091238 (Fair). Data were also provided (in part) by the Human Connectome Project, WU-Minn Consortium  funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; OHSU Fellowship for Diversity and Inclusion in Research Program (Oscar Miranda-Dominguez); and by the McDonnell Center for Systems Neuroscience at Washington University.


The development of biotechnological protocols based on cationic surfactants is a modern trend focusing on the fabrication of antimicrobial and bioimaging agents, supramolecular catalysts, stabilizers of nanoparticles, and especially drug and gene nanocarriers. The main emphasis given to the design of novel ecologically friendly and biocompatible cationic surfactants makes it possible to avoid the drawbacks of nanoformulations preventing their entry to clinical trials. To solve the problem of toxicity various ways are proposed, including the use of mixed composition with nontoxic nonionic surfactants and/or hydrotropic agents, design of amphiphilic compounds bearing natural or cleavable fragments. Essential advantages of cationic surfactants are the structural diversity of their head groups allowing of chemical modification and introduction of desirable moiety to answer the green chemistry criteria. The latter can be exemplified by the design of novel families of ecological friendly cleavable surfactants, with improved biodegradability, amphiphiles with natural fragments, and geminis with low aggregation threshold. Importantly, the development of amphiphilic nanocarriers for drug delivery allows understanding the correlation between the chemical structure of surfactants, their aggregation behavior, and their functional activity. This review focuses on several aspects related to the synthesis of innovative cationic surfactants and their broad biological applications including antimicrobial activity, solubilization of hydrophobic drugs, complexation with DNA, and catalytic effect toward important biochemical reaction. Cationic surfactants are amphiphilic compounds, which can dissociate in water with the formation of surface-active cations. These molecules have the capacity of self-assembling , being wOccurrence of positively charged fragments in amphiphilic scaffold is responsible for their attractiveness in nanotechnological applications as antimicrobial and bioimaging agents ,6, corroDespite the fact that general positive trend occurs in the development of biotechnological protocols based on cationic surfactants including their use in the treatment of virulent diseases, the toxicity of cationic amphiphiles remains the main problem preventing their wide practical applications. Starting with the first and second generations of cationic charged liposomes , preclinA series of works focusing on the application of cationic surfactants in drug delivery have been recently reviewed , with emOne of the promising approaches in the design of building blocks for biomedical applications, which include formulations for drug delivery, is the creation of new multifunctional environmentally friendly, cleavable, green, and less toxic cationic surfactant systems answering the biotechnological criteria and improving biocompatibility, solubility, bioavailability, and biodegradability of therapeutics ,36,37. TIn recent years, particular attention is focused on gemini surfactants due to their advanced structure-activity correlation, superior aggregation capacity, and versatile morphological behavior ,43. Unli1a) are based on two molecules of the prototype quaternary ammonium surfactant (QAS), cetyl trimethyl ammonium bromide (CTAB), or dodecyl trimethyl ammonium bromide (DTAB), linked by an alkyl spacer at the ammonium group. Examples of such structures are presented in m-s-m, where m and s represent the number of carbon atoms in alkyl chains and in polymethylene spacers, respectively. The quaternary ammonium group can also be contained in an imidazole heterocycle (1b). In this case, a long alkyl chain providing lipophilicity is linked to 3’ nitrogen in the imidazole ring, and a spacer links 1’ quaternary ammoniums. The simplest QA gemini surfactants (1c), where the spacer links the monomers at hydroxyl group of glucose moiety , or, or1e) , especially those bearing methylimidazolium (mim) cation. Dicationic imidazolium surfactants were reported to be used as supramolecular models of anionic abiotic receptors and exhibit high binding activity to anionic drugs exemplified by valproate . 14mimBr in aqueous solution has been evaluated in the presence of sodium salicylate . In. Inε-acyα quaternary ammonium octane based surfactants resorcine [3c and 4c in nutrient broths (Hottinger broth (pH = 7.2) and Sabouraud dextrose broth (pH = 5.6)) up to 60 times [Additives are shown to affect the CMC values. For aqueous esorcine ,145,146,esorcine  capable 60 times .3a, 3b, and 3d, β ranges from 0.67 to 0.84, while for 3c it changes from 0.81 to 0.91 [3a, 3b, and 3c, respectively [3b concentrations the larger micelles are formed that are characterized by higher numbers of aggregation. This is confirmed by the fluorimetry data indicating that for the 3b concentrations of 5 × 10−3, 7.5 × 10−3, and 2.5 × 10−2 M aggregation numbers equal 40, 59 and 114, respectively.Apart from CMCs, the degree of counter-ion binding β, radiuses of quaternized DABCO derivative aggregates and number of aggregations are determined. For  to 0.91 . NMR difectively ,153, i.eectively . At high3c has been shown to belong to amphotropic compounds capable of forming the mesophase of different types, i.e., thermotropic and lyotropic. It has been found that for lyotropic liquid crystals the wider temperature range is observed as compared to thermotropic phase. The existence of lyomesophase within the wide temperature range extends the application of these systems as matrix for the design of nanomaterials and models of membranes in biotechnological protocols. These data are in line with unusual structural behavior of hydrophobized DABCO derivatives highlighted by the dynamic light scattering data. For 3d ensembles, hydrodynamic diameter has been recorded in the range from 180 to 280 nm and was dependent on the age of the solutions. An increase in the concentration of 3c was followed by the decrease in the size of aggregates from 180 to 135 nm. The hydrodynamic diameter of 4-Et particles at concentration around CMC is ca. 110–160 nm. The monitoring of the solutions with time revealed even higher aggregation of particles. The increase in the concentration of 4-Et was followed by the substantial decrease in the size of aggregates, up to 3–4 nm [4b solutions supports our suggestions on the change of the morphology of aggregates.o 3–4 nm . SimilarSolubilization capacity of aggregates is a key property responsible for the use of cationic surfactants as nanocarriers. This stimulates the search for novel effective formulations for solubilization of hydrophobic drugs and diagnostic probes, and therefore the elucidation of structure-activity relation is a challenging task. While the factor of hydrophobicity of surfactants in terms of alkyl tail length is discussed in literature, the influence of structure of head groups is less studied and understood . In our Solubility of Orange OT linearly increases with alkyl chain length of surfactants and follows the relations:This may be explained by the fact that regardless of the similarity of CMC values for trimethyl ammonium-n and DABCO-n series, their structural behavior differs markedly. Moreover, DABCO based cationic surfactants exhibit superior solubilization properties over cationic surfactants with triphenylphosphonium head groups , althougThe decrease in solubilization capability of di-CS-n with the same alkyl chain may result from their lower aggregation numbers and lower packaging in di-CS-n micelles.Many advantages in the development of effective drug delivery systems may be obtained upon the design of mixed assemblies. Nowadays, the interest in mixed compositions has markedly increased due to the development of novel direction of supramolecular chemistry focusing on the formation of supramolecular amphiphiles . Growing3c starts to associate at the lower concentration and undergoes further morphological transitions with an increase in the concentration [3c are capable of binding the organic probe, while mixed system where the surfactant is a minor component shows no binding capacity towards Orange OT  surfactants. Catalytic activity of the systems based on quaternized derivatives of DABCO is exemplified by basic hydrolysis (in water) and aminolysis (in chloroform) of phosphorus acid esters  monitore3c) and their mixtures has shown the catalytic effect on the hydrolysis of phosphorus acid esters. It was established that the presence of La(NO3)2 leads to a 650-fold increase in the catalytic effect [Our studies focusing on the evaluation of the structure-activity relations revealed that the cationic surfactants catalyze the hydrolysis of NBCP . Their cc effect . The preSt. aureus, B. cereus, and E. coli, respectively). Generally, bacterial strains were the most sensitive toward tetradecylrimethylammonium bromide in series of n-alkyltrimethylammonium bromides [St. Aureus, for which the transition from CTAB to quaternized quinuclidine and monoquaternized DABCO derivatives provide a tenfold increase in bactericidal activity. Much higher antifungal activity exemplified by Tr. gipseum and C. albicans should also be noted for 3d as compared to CTAB. Fungistatic activity of 3d toward these strains is by two-fold and four-fold higher and fungicidal activity is by 16-fold and 10-fold higher than those for CTAB. The bactericidal and fungicidal activity of Q-Nuc-18 is 1.95 μg·mL−1. This value is much higher than for its DABCO-n analogues. Q-Nuc-18 has bactericidal and fungicidal activity two times (against St. aureus) and eight times (against B. cereus) higher than antibiotics Norfloxacin and antifungal Ketoconazole. Q-Nuc-16 has the highest bactericidal activity. It is six times (against St. aureus) and 15 times (against B. cereus) higher than the bactericidal activity value of Norfloxacin [In addition to the aggregation and catalytic properties, antimicrobial activity of quaternized DABCO derivatives has also been studied, whereby the correlation of antimicrobial and aggregation properties is analyzed . The bacbromides  and towabromides . The inffloxacin .3c) to diquaternized derivatives of DABCO (4c-Et) results in four-fold decrease in antifungal activity toward Tr. gipseum and in ten-fold decrease toward C. albicans. At the same time, antimicrobial activity toward B. Cereus, E. coli, and St. Aureus remains practically the same. Data obtained demonstrate that the introduction of bicyclic polar fragment into surfactant platform may be of interest from the viewpoint of the design of antimicrobial preparations  of little toxicity. The highest effect can be achieved by the increase of alkyl chain length and optimization of hydrophilic-lipophilic properties [−1. The MICs of 2-Dabco-2-Dabco-12 are 3.9, 7.8, and 31.3 µg/mL against St. aureus, B. cereus, and E. coli, respectively. Likely this is due to a different mechanism of action of these surfactants. Four charged nitrogen atoms and two alkyl chains of n-Dabco-2-Dabco-n may accommodate faster interaction and penetration of DABCO-surfactants through the bacterial cytoplasmic membrane. These results clearly indicate that the antibacterial activity of DABCO-surfactants is strongly affected by their structure .Second charge moiety exerts a negative influence on antifungal activity, e.g., the transition from monoquaternized derivatives of DABCO . Noteworthy, the selection of papers for this review judged from the idea to reflect key trends in the field of bio- and nanotechnological applications of amphiphile-based systems, especially those positively charged. As can be seen, these trends focus on the development of drug delivery systems answering the criteria of green chemistry and biomimetic design. Therefore, the majority of strategies are aimed at the fabrication of soft and smart nanosized constructions, with the minimization of concentration of building blocks and their side effect attained. Moreover, it is still challenging to prepare nanocarriers with acceptable toxicological profile. In future studies, research towards the optimization of the formulations, and the study of structure-properties correlations are strongly needed, which brings to the forefront the systematic studies involving homological series of amphiphilic compounds and their directed functionalization. A steady trend that is assumed to be preserved consists in the use of gemini and polycationic compounds allowing for markedly diminish the usage of self-assemble units due to their low aggregation threshold. The same is true for the very promising compounds bearing cleavable moiety, e.g., ester and amide groups. Meanwhile, biomimetic approach assumes the wider use of natural components; therefore, amphiphiles bearing biofragments remain of special interest. Separate line in nanomedicine strategy involves the use of amphiphilic peptides and peptide-conjugated formulations for delivery of both hydrophilic and hydrophobic therapeutic molecules. Noteworthy that preparation of drug delivery systems involving biological units may be administered through both covalent and non-covalent protocols. While the former provides more advantages in functional activity, the latter is less expensive and assumes the simpler and faster experiments. Therefore, the parity is probably expected to be preserved between these strategies. To sum up, one of the most relevant applications of cationic surfactants is the design of modified nanocontainers for drug and gene delivery. However, more in-depth studies need to be done, such as in vivo experiments to evaluate functional activity of the loaded cargos, due to the achievement of synergetic structural behavior and multidrug delivery with stimuli responsive activity.


Psychiatric comorbidities are common in individuals with attention-deficit/hyperactivity disorder (ADHD). In this study, we sought to evaluate the effects of medication and childhood ADHD subtypes on psychiatric comorbidities among adults with ADHD as compared to healthy adult controls. We assessed 121 drug-naïve adults with ADHD, 93 treated adults with ADHD, and 145 healthy controls (age 18–36 years) using semi-structured psychiatric interviews, intelligence tests, and medical records. Drug-naïve adults with ADHD had more comorbidities than treated adults with ADHD and controls. Childhood ADHD-combined subtype, relative to ADHD-inattentive subtype, was associated with higher risks of comorbidities. Current medication treatment was associate with a higher risk for anxiety disorders, and longer treatment duration was associated with lower risks of mood disorders and sleep disorders. Our results indicate that no medication treatment, short treatment duration, and childhood ADHD-combined subtype are associated with increased risks for psychiatric comorbidities among adults with ADHD. Symptoms of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood among adults with this disorder . The preThe existing literature has shown that adults with ADHD, relative to controls, are more likely to have psychiatric disorders , 8. HowePrevious clinical trials have demonstrated the benefits and efficacy of medication in reducing clinical symptoms of ADHD  and imprResearch on the associations between ADHD subtypes and psychiatric comorbidities in children and adolescents has suggested differential comorbid patterns  and braiTaken together, little is known regarding the effects of medication, the duration of pharmacotherapy, and childhood ADHD subtypes on the psychiatric comorbid patterns in adults with ADHD. Hence, this study aimed to address these gaps in the literature by (1) examining group differences in psychiatric comorbid conditions among drug-naїve adults with ADHD, adults with ADHD treated with medication, and controls; (2) examining the effect of medication duration by comparing drug-naїve adults with ADHD, adults with ADHD treated longer than one year and those treated shorter than one year, and controls, in terms of psychiatric comorbid conditions; and (3) comparing adult psychiatric outcomes among adults with different childhood ADHD subtypes and controls.The sample consisted of 214 adults with a clinical diagnosis of ADHD according to the DSM-IV diagnostic criteria and 145 healthy adult controls aged 18–36 years. Adults with ADHD were recruited from three sources: (1) a cohort of patients with ADHD assessed during their childhood ; (2) patThe new patients were screened using the Chinese version of the 6-item Adult ADHD Self-Report Scale-V1.1 , 60, folDetailed information about the medication history for treating ADHD  and age onset of ADHD were included in the modified adult ADHD supplement of the Chinese K-SADS-E. Both ADHD participants and their parents received psychiatric interviews for the treatment history of medications mentioned above. The treatment data were validated by medical records in the NTUH if available; otherwise, they were validated by Taiwan’s National Health Insurance Claims data, which covers 99.9% of the population in Taiwan. Current use was defined as the presence of medication use for treating ADHD (methylphenidate or atomoxetine) in the past month regardless of the usage history prior to that. Ever use was defined as no medication use for treating ADHD in the past month but the use of these medications prior to the past month. Duration of use was defined as the total number of days on medications.Adult healthy controls were recruited by advertisements on the internet, newspapers, and flyers at the colleges and public places based on the age and gender distributions of the ADHD group. They were screened by telephone interviews to rule out past or current ADHD symptoms, followed by clinical assessments and psychiatric diagnostic interviews using the Conners Adult ADHD Diagnostic Interview and the adult ADHD supplement of the Chinese K-SADS-E to ensure that they did not have lifetime or current diagnosis of ADHD. They also received the Chinese SADS for assessing other non-ADHD diagnoses.All participants who had an IQ < 80 ascertained by the Wechsler Adult Intelligence Scale-Revised, had any serious medical illness such as cardiovascular disease, a history of learning disability, psychosis, pervasive development disorder or intellectual disability were excluded from the study.The Research Ethics Committee of National Taiwan University Hospital  approved this study before its implementation. After detailed explanations of the study, participants who provided written informed consent were recruited into the study. The final sample included 93 adults with ADHD who had been diagnosed with ADHD during childhood and treated for ADHD (treated ADHD), 121 adults with ADHD who have not been treated for ADHD (drug-naïve ADHD), and 145 adult controls without ADHD.The Chinese K-SADS-E for DSM-IV demonstrated good reliability and validity and had been widely used in a variety of clinical –68 and enever; 1, rarely; 2, sometimes; 3, often; 4, very often. The psychometric property of the Chinese ASRS has been established in a sample of 1031 young males from an army base and 3298 young adults from two colleges in northern Taiwan [The ASRS, an 18-item self-reported scale, was developed in conjunction with the revision of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). The ASRS consists of two subscales, inattention (9 items) and hyperactivity-impulsivity (9 items), according to the 18 DSM-IV ADHD symptoms criteria. Each item asks how often a symptom occurred during the past six months on a 5-point Likert scale: 0, n Taiwan . It is wn Taiwan , 71, 74.Data were analyzed using SAS 9.1 . To examine sample characteristics among groups including age, gender, IQ, childhood and adulthood ADHD symptoms, and SES, we conducted chi-square tests  and analyses of variance . We first compared sample characteristics between 214 adults with ADHD (drug-naïve and treated) and 145 healthy controls, and then compared across 3 groups: (1) drug- naïve ADHD (n = 93); (2) treated ADHD (n = 121); and (3) healthy controls (n = 145) . When siTo examine the association between comorbidities and treatment status we compared the three groups (drug-naïve ADHD vs. treated ADHD vs. controls) on comorbid disorders . To furtADHD and controls had higher Full-scale IQ, Performance IQ, Verbal IQ (control only) and years of education than treated ADHD. Males were more predominant in treated ADHD than in drug-naïve ADHD and controls. Drug-naïve ADHD had more severe inattentive and hyperactive-impulsive (adulthood only) symptoms during childhood and adulthood than treated ADHD. Because of the between-group differences in age, sex, educational years, and Full-scale IQ, we controlled for these variables in our subsequent analyses.Participants with childhood ADHD-C were more likely to have tic disorder, panic disorder, and alcohol use disorder than those with childhood ADHD-I and controls. Moreover, participants with childhood ADHD-C were more likely to have eating disorder than controls and more likely to have ODD, CD, and sleep disorders than childhood ADHD-I .The psychiatric comorbid patterns across different ADHD subtypes at the current assessment (adult ADHD subtypes) are presented in Multivariate analyses revealed that childhood ADHD-C was associated with a higher risk of ODD, CD, and sleep disorders. Current use of medication was associated with an higher risk of anxiety disorders. Longer duration of medication use was associated with lower risks of mood disorders and sleep disorders . UnivariThe current study is one of the few studies that examined comprehensively the psychiatric comorbid patterns in adults with ADHD with regards to the effects of treatment history and duration, as well as childhood ADHD subtypes. We found that adults with ADHD, in general, had significantly more comorbid psychiatric conditions than controls. Drug-naïve adults with ADHD, relative to treated ADHD and controls, had more core ADHD symptoms during childhood and adulthood (except for childhood hyperactivity/impulsivity) and more psychiatric comorbidities, particularly GAD, mood disorders, adjustment disorders, and sleep disorders. Childhood ADHD-C subtype, relative to ADHD-I, was associated with higher risks of ODD, CD, OCD, alcohol use disorder, and sleep disorders. Importantly, we found that childhood ADHD-C was a strong correlate of several common comorbid conditions including ODD, CD, and sleep disorders. Current use of medication and a shorter duration of medication use were associated with anxiety and mood disorders, respectively.Similar to our adolescent ADHD study  and prevNo studies have examined the association between treatment effects and panic disorder or specific phobia in adults with ADHD. Our result contributes to the literature by showing that panic disorder was more prevalent in treated ADHD adults than controls. Whether this finding is due to treatment-induced panic-like side effects requires further clarification from future research. Another novel finding is that specific phobia was more prevalent in drug-naïve ADHD and ADHD-TS than controls, suggesting that long-term treatment (> one year), relative to no treatment or short-term treatment (≤ one year), was associated with a decreased risk of specific phobia in adults with ADHD. A prospective follow-up study of these patients is warranted to test the causal effect i.e., whether longer treatment duration indeed decreases the risk of specific phobia.Previous studies reported that patients with ADHD treated for at least one year did not differ from drug-naïve ADHD in the risk of MDD  and thatOur finding that current use of medication increases the risk of anxiety disorder is contradictory to the studies showing that treatment decreased , 23, 78 Our findings strongly support more instances of psychiatric disorders in adults with ADHD-C than adults with ADHD-I , 54. SpeThis study is the first one to examine a wide range of psychiatric comorbidities by using (semi-)structured diagnostic interviews rather than self-reported questionnaires among adults with ADHD and to investigate comprehensively the effects of treatment and treatment duration, as well as childhood ADHD subtypes, on the psychiatric comorbid patterns. Despite this, several limitations merit comments. First, the directionality and causality of the significant findings remain to be determined. Second, although our longitudinal pilot study showed a high correlation between adolescent/mother reports and adult self-reports about the participants’ ADHD symptoms , recall Our findings suggest that ADHD often persists into adulthood and is still associated with high psychiatric comorbidity. Treatment with ADHD medications may reduce comorbidity. Moreover, childhood ADHD-C is associated with a greater risk of adult comorbidities than ADHD-I and is one of the significant correlates of adult comorbid conditions. The findings suggest that for adult ADHD, medication treatment should be considered as one of the necessary treatment modalities to prevent the development of psychiatric comorbid conditions. For children with ADHD-C, medication treatment may likewise be helpful to minimize the risks of adverse psychiatric outcomes in adulthood, decreasing social impairment and improving life quality .S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.


The cognitive capacity to change perspective is referred to as theory of mind (ToM). ToM deficits are detectable in a variety of psychiatric and neurological disorders. Since executive abilities are closely associated with ToM skills, we suspected that due to a common neuropsychological basis, ToM deficits exist in treatment‐naïve adults with attention‐deficit/hyperactivity disorder (ADHD).N = 30) in tasks assessing executive functions , empathy skills , and ToM  was compared with that of a healthy control group (N = 30) matched according to basic demographic variables.Performance of treatment‐naïve adults with ADHD (p < .05). However, no performance differences were found with regard to ToM .Compared to healthy controls, treatment‐naïve adults with ADHD showed deficits in various executive functions and the ability to empathize (all Since studies in juveniles with ADHD often show impaired ToM performance, it is conceivable that ToM deficits may become attenuated due to neuronal development in adolescence. Furthermore, our findings imply that ToM impairments, even when present in adult ADHD, appear to be independent of executive deficits and might be explained by comorbid disorders. This study explored the extent to which social interaction problems of treatment‐naïve adults with ADHD can be attributed to deficits in theory of mind using established neuropsychological tests. The results revealed that adults with ADHD showed impairment in various executive functions and the ability to empathize but no theory of mind deficits. Our findings imply that ToM impairments, even when present in adult ADHD, appear to be independent of executive deficits and might be explained by comorbid disorders. The lack of empathy skills in treatment‐naïve adults with ADHD is a robust result.Contrary to previous results, unmedicated adult ADHD patients showed no ToM deficits.We did not assess levels of social functioning. Future studies should therefore assess the extent to which there is any impairment in downstream functions and to what extent these issues are related to ToM or empathy deficits.This exploratory study with relatively small sample sizes provides the first evidence of differential associations between cognitive and emotional perspective taking with executive functions but requires further replication in larger study samples.1The term social cognition describes the general ability to visually and auditorily perceive, interpret, and behave based on important stimuli in a social context  due to inattentive, impulsive, or generally socially inadequate behaviour  and cognitive perspective taking (ToM). Thus, adult empathy was assessed by the Cambridge Behaviour Scale  is a video‐based psychometric instrument for the measurement of mental state attribution skills, particularly ToM , the nonparametric Mann–Whitney U test was performed. All statistical analyses were two‐sided with the significance threshold set at .05 and were conducted with SPSS Statistics, version 24.0.Frequencies were used as descriptive statistics for categorical data. Mean and standard deviations were calculated for continuous data. Intergroup comparisons were carried out using independent Student's 33.1M = 34.50 years; SD = 6.81). The average verbal intelligence reached 108.91 (SD = 7.67) and 112.10 (SD = 7.86) for practical intelligence. The average school education was 11.10 years (SD = 1.56), and the average amount of higher education was 3.30 years (SD = 1.55). Nine of the 30 patients stated that they smoked.The patient group included 30 adult treatment‐naïve patients with a confirmed ADHD diagnosis based on the DSM‐IV‐TR  consisted of 15 males and 15 females. They were between 18 and 57 years old . Verbal intelligence averaged 110.22 (SD = 8.72), and practical intelligence averaged 108.87 (SD = 9.03). The control group had an average amount of school education of 12.07 years (SD = 1.55) and 3.45 years (SD = 2.26) of higher education. There were five smokers in the control group.The ADHD patient group and the control group were matched by demographic variables such as age, sex, IQ, and duration and level of education in order to control for the influence of those variables. The control group  = 0.617, p = .54), implying similar visual scanning abilities in both groups. The TMT‐B, a test that requires attention shifting/cognitive flexibility as well as working memory skills  = −0.544, p = .588), but patients committed more mistakes (t (58) = −2.08, p = .042*).In detail, a nonsignificant difference occurred when comparing the performance on the TMT‐A between the two groups , thus showing impaired empathy .In contrast, there were no significant differences between adult participants with ADHD and healthy controls in terms of ToM performance in the MASC, although patients performed slightly poorer in particular MASC tasks than controls Table . However3.4We calculated Spearman's Rho between ToM, empathy, and the various variables of executive functioning separately for ADHD patients and healthy controls. Within the healthy control group, we could not show any correlations between ToM, empathy, and executive functions. Correlations between empathy and executive measures for the ADHD group are displayed in Table t = −2.6045, p = .0117), empathy, and TMT‐B  as well as an almost significant moderating effect on the relation between empathy and executive control questions . When analyzing ToM, we were not able to prove that cognitive flexibility as measured by the TMT‐B had a different influence on ToM in both groups .Afterward, we conducted moderation analyzes, a form of multiple regression analysis. We defined empathy and ToM as dependent variables and group membership as moderating variable. We set TMT‐A, TMT‐B, and executive control questions as independent variables/predictors. We planned to investigate how group affiliation influenced the relationship between dependent and independent variables. Regression models were calculated in which a significant interaction demonstrates a significant influence of the moderating variable. Group affiliation showed significant influences on the relation between empathy and TMT‐A  cognitive performance. Furthermore, a differentiation in terms of sex would be conceivable, as well as a critical examination of the transitional stages not only from child to adulthood but also from adulthood to the senium.As Gonzalez‐Gadea et al.  and BoraIn addition to cognitive‐behavioral therapy approaches, positive drug effects should be investigated. For example, a study by Maoz et al.  found thThe comparatively small sample size of our study bears the risk of being underpowered to show clear differences between ADHD and healthy controls. Therefore, our results require further replication in larger study samples.BK has received honoraria for lectures from Medice and Servier. In addition, he is an advisory board member for Medice and Servier. MAH has received honoraria from Medice for the compilation of educational brochures. The other authors have nothing to report or to disclose.