Previous studies have shown smaller brain volume and less gray matter in children with attention-deficit/hyperactivity disorder (ADHD). Relatively few morphological studies have examined structures thought to subserve inhibitory control, one of the diagnostic features of ADHD. We examined one such region, the pars opercularis, predicting a thinner cortex of the inferior frontal gyrus (IFG) in children with ADHD.Structural images were obtained from 49 children  aged 9 though 15 years. Images were processed using a volumetric pipeline to provide a fully automated estimate of regional volumes of gray and white matter. A further analysis using FreeSurfer provided measures of cortical thickness for each lobe, and for 13 regions in the frontal lobe.Relative to controls, children with ADHD had smaller whole brain volume and lower gray matter, but not white matter, volumes in all lobes. An analysis of frontal regions showed a significant interaction of group by region. Planned contrasts showed bilateral thinner cortex in the pars opercularis in children with ADHD.Children with ADHD showed both diffuse and regional gray matter abnormalities. Consistent with its putative role in response inhibition, the cortex of the pars opercularis was thinner in children with ADHD who, as expected, had significantly poorer inhibitory performance on a Go/No-go task. These differences held for both hemispheres raising the possibility that a developmental abnormality of IFG might drive development of inhibition difficulties. Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting between 3% and 5% of children and young persons. It is characterized by pervasive and developmentally inappropriate levels of inattention, impulsivity, and hyperactivity and wide-ranging behavioral and cognitive impairments, including deficits in working memory, inhibitory control, and altered motivational style.The frontal lobe is an important focus of research in ADHD for a number of reasons. Converging evidence implicates dopaminergic dysfunction of fronto-striatal circuits in the pathogenesis of the disorder.Several fronto-cortical regions, including the ventrolateral prefrontal, dorsolateral prefrontal, and anterior cingulate cortex (ACC), are important in attention. In particular, several studies have highlighted the role of the ventrolateral regions of the inferior frontal gyrus (IFG)—particularly the right IFG—as being crucial for inhibiting behavioral responses.Further support for the importance of the pars opercularis in inhibitory control is provided by a recent repetitive transcranial magnetic stimulation (rTMS) studyAlthough these findings highlight the significance of the IFG in inhibitory control, a number of other regions appear to be important for this function, including pre–supplementary motor area (preSMA) and right dorsolateral prefrontal and inferior parietal areas, with activation in the latter two regions being particularly pronounced when working memory load is high.Here, we used MRI to obtain a number of global and regional measures of brain structure in a clinical group of children and adolescents with ADHD characterized by clinical impulsivity/hyperactivity and inattention (DSM-IV combined subtype) and in healthy controls. In accordance with previous studies and the heterogeneous nature of the disorder, we predicted smaller brain volume and global reductions in GM in participants with ADHD. In addition, based on the putative role of the IFG in inhibitory controlEthical approval was granted by the local Research Ethics Committee and Research and Development Departments of the Nottinghamshire Healthcare and Lincolnshire Partnership NHS Trusts. After complete description of the study, written informed consent and verbal assent was obtained from parents and children, respectively. Thirty children with ADHD and 33 controls taking part in an fMRI/EEG study  and exclusion criteria . Eligible participants were invited to attend an assessment session in which we administered the Development and Well Being Assessment [DAWBA]ADHD diagnosis was confirmed or overturned following a clinical consensus diagnostic meeting involving CH and another experienced child and adolescent psychiatrist. This included a full review of the child's medical history, parent and teacher DAWBA transcripts (including computer generated predictions) and questionnaires. Only right-handed participants with a DSM-IV diagnosis of ADHD combined subtype and an established positive response to stimulant medication  were included. Diagnosed or suspected comorbidities were investigated where necessary, and any participants with psychosis, bipolar disorder, major depression, Tourette syndrome, Autistic Disorder/Asperger's Disorder, major head trauma or epilepsy were excluded. Participants with comorbid oppositional defiant disorder (ODD), conduct disorder (CD), and anxiety disorder were included. A separate session assessed intelligence, reading ability and handedness using, respectively, Weschler Abbreviated Scale of Intelligence (WASI), Test of Word Reading Efficiency (TOWRE), and Annett Handedness Questionnaire. Any subjects with a full scale IQ <70 were excluded.Letters detailing the study were sent to approximately 600 families of children in primary and secondary schools in the Nottinghamshire region. From an initial sample who volunteered to take part, we selected a group of right-handed controls matched for age (±6 months), sex, and parental socio-economic status (SES) to a member of the ADHD group. Parental SES was assessed using the eight groups identified in the ONS SES manual , combined to form four subgroups  to enablParticipants undertook additional tasks (not reported in this paper) on two separate days as part of the fMRI/EEG study, in which testing was conducted on and off stimulant medication, the order of which was counterbalanced across subjects. Therefore, approximately half on the structural scans for the ADHD group were taken while the subjects were on medication (n = 13), while the remainder (n = 12) were scanned following a ∼36-hour stimulant-medication withdrawal. No effects of medication status at the time of scanning on brain structure were predicted for the ADHD group; controls were never medicated.T1-weighted (T1W) brain images in the sagittal plane were obtained with a Philips Achieva 1.5-T MRI scanner with an eight-channel SENSE head coil using a 3D TFE sequence with the following parameters: 160 contiguous slices; TR/TE 9.9/3.7 ms; matrix size, 256 × 256; voxel size, 1 × 1 × 1 mm. Head movement was minimized by the use of foam pads placed within the head coil.The acquired images were processed using a pipeline adapted from the Montreal Neurological Institute (MNI) approach.Estimates of cortical thickness were obtained using FreeSurfer.GG). All reported analyses include data from all eligible participants. When the analyses were repeated omitting the one female ADHD–control pair, the pattern of results remained the same.All statistical analyses were conducted using SPSS v.16 . Volumes of WM and GM and mean cortical thickness were computed for each lobe and combined across the left and right hemispheres. To ascertain the presence of group differences in frontal cortex, particularly inferior frontal gyrus (IFG), we also tested differences between the two groups in cortical thickness in 13 frontal regions segmented by the FreeSurfer. If the data violated the assumptions of sphericity, Greenhouse-Geisser adjusted degrees of freedom were used and a corrected p value was reported (pt (50) = 4.27, p = .0003 and FSIQ was also used as a covariate in all subsequent analyses.There were no significant differences in age, sex, or socioeconomic status (SES) between the two groups . Because3, SD = 118.19; CTRL = 1387.89 cm3 SD = 112.12). Age was a significant predictor of brain volume, with larger brains in the older children. Including a quadratic term for age did not improve the fit of the model.An analysis of covariance (ANCOVA) using the between subjects factor GROUP (ADHD vs. CTRL) and the covariates AGE and full-scale IQ (FSIQ), returned significant main effects of GROUP  and AGE  but not FSIQ [F<1]. Participants with ADHD had smaller total brain volume than CONTROLS  and frontal lobe   relative GM volumes were significantly different between the two groups. The same was also true when total surface  area was entered as a covariate (instead of brain volume). Overall, total relative GM volume is significantly lower in ADHD children, as compared with CONTROLS, after covarying for surface area (or brain volume), surface ratio, and mean thickness.Absolute GM volumes for each lobe were entered into a multivariate analysis of covariance. There were significant main effects of AGE, F  = 6.03, p = .001 and GROUP, F  = 5.71, p = .001. Younger children had lower GM volume than older children, and children with ADHD had less GM than CONTROLS. Univariate analysis showed smaller GM volumes in all four lobes in ADHD, as compared with CONTROLS: Frontal ; Parietal ; Temporal  and Occipital  . AlthougF<1). The smaller brain volume in the ADHD cases appears to be driven by lower GM volume in all lobes.When the analysis was repeated using WM volume, there was no main effect of GROUP  = 6.00, p = .018; children with ADHD had significantly thinner cortex in the pars opercularis than CONTROLS . There was no significant difference in the thickness of the pars opercularis between the left and right hemisphere, as evidenced by the nonsignificant GROUP × HEMISPHERE interaction (F = 1.1) but univariate analysis conducted on each hemisphere separately showed a significant main effect of GROUP in the right hemisphere, F  = 5.79, p = .02,and a trend in the left hemisphere, F  = 3.30, p = .076. Including a quadratic term for age improved the fit of the model, whereby the left pars opercularis had a nonsignificant positive value and the right pars opercularis had an inverted U function (significant quadratic effect) of age, peaking at around 148 months  = 2.49, p(GG) = .024. In a planned comparison, the thickness of the pars opercularis was compared with the mean thickness of all the other frontal areas and a significant effect was found, F  = 4.58, p = .038. Children with ADHD had thinner cortex in the pars opercularis relative to CONTROLS in both hemispheres. The effect sizes for each of the 13 regions are presented in Mean cortical thickness across the 13 frontal cortical regions  were then entered into a 2 (GROUP) × 13 (REGION) × 2 (HEMISPHERE) repeated-measures ANCOVA using the covariates AGE, and FSIQ and returned a significant REGION × GROUP interaction, A vertex-based analysis using the between-subjects factor GROUP failed to reveal any significance difference in cortical thickness for any voxels in any of the lobes after correcting for multiple comparisons across the entire cerebral cortex.On a Go/No-go task, inhibition rates were significantly lower in children with ADHD than controls . PearsonConsistent with previous studies,a priori interest in the frontal lobe, specifically, the pars opercularis, because of its putative role in inhibitory control.The global lower GM volume in the ADHD group might be explained using a model of delayed brain maturation.a priori regions or to detect small effects post hoc.The strengths of this study include a well-defined clinical sample, the inclusion of only combined type ADHD and careful matching of controls. There are, however, also some limitations. Although the sample size is larger than that of many similar studies, it lacked the statistical power required to explore multiple With respect to medication, in one of the largest morphologic studies to date,Our findings demonstrate that an ADHD combined type subgroup, with clinical features including impulsivity/hyperactivity have both a generalized deficit in gray matter compared with healthy controls, but there is some evidence of nonuniformity, with the deficits being most marked in IFG. Future work using a single heterogeneous group with a spectrum of severity of impulsivity deficits would enable us to test for the anatomical correlates of impulsivity in ADHD.


Theories of attention-deficit/hyperactivity disorder (ADHD) posit either executive deficits and/or alterations in motivational style and reward processing as core to the disorder. Effects of motivational incentives on electrophysiological correlates of inhibitory control and relationships between motivation and stimulant medication have not been explicitly tested.n = 28) and matched typically developing children (CTRL) (n = 28) performed a go/no-go task. Electroencephalogram data were recorded. Amplitude of two event-related potentials, the N2 and P3 (markers of response conflict and attention), were measured. The ADHD children were all stimulant responders tested on and off their usual dose of methylphenidate; CTRLs were never medicated. All children performed the task under three motivational conditions: reward; response cost; and baseline, in which points awarded/deducted for inhibitory performance varied.Children (9–15 years) with combined-type ADHD (p = .1). Interactions between motivation and diagnosis/medication were nonsignificant (p > .1).There were effects of diagnosis (CTRL > ADHD unmedicated), medication (on > off), and motivation (reward and/or response cost > baseline) on N2 and P3 amplitude, although the N2 diagnosis effect did not reach statistical significance  amplitudes of control subjects. These results suggest that, on these measures, motivational incentives have similar effects in children with ADHD as typically developing CTRLs and have additive effects with stimulant medication, enhancing stimulus salience and allocation of attentional resources during response inhibition. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of hyperactivity, impulsivity, and inattention. Children with ADHD exhibit a range of cognitive difficulties, including impaired inhibition of the prepotent motor response in go/no-go and stop signal tasks , leadingChildren with ADHD also show atypical regulation of motivational state: they respond to rewards when they are delivered immediately and with regularity but are less sensitive to rewards that are delayed or intermittent . It has We investigated effects of motivation on neural correlates of response conflict and attention in ADHD using a go/no-go paradigm, in which two motivational conditions and a baseline (low motivation) condition were presented repeatedly, randomized within session. Electroencephalography (EEG) data were collected while children performed the task; amplitudes of N2 and P3 were measured. We predicted significantly smaller N2 and P3 amplitudes in the ADHD group than the control group. Incentives were delivered continuously and immediately. We therefore predicted that if inhibitory deficits are related to impaired motivation in ADHD, incentives would significantly enhance amplitudes of the ADHD group to at least the same level as the baseline (low motivation) amplitudes of the control group.In addition, we investigated relationships between stimulant medication (methylphenidate [MPH]) and motivation in the ADHD group using a within-subjects design. Methylphenidate is believed to increase availability of dopamine in the striatum, enhancing salience of task-relevant stimuli , improviParticipants were 28 children with ADHD , aged 9 to 15 years, and 28 typically developing control subjects matched on age, gender, and socioeconomic status (SES). Ethical approval was granted by the Multicentre Research Ethics Committee (MREC). Informed written parental consent and verbal participant assent were obtained from all participants. n = 13, 46%), and conduct disorder  were not excluded.Letters detailing the study were sent via local schools to parents. Right-handed children with no psychiatric diagnosis were selected for further assessment if they matched demographically a member of the ADHD group. Exclusion criteria were those listed above for the ADHD group in addition to score >5 on the hyperactivity subscale of the SDQ and/or score >1 SD above normative means on the Conners Rating Scale-Revised (Long Form) ADHD index. Anxiety, depression, and conduct problems were not excluded, although no control subjects met criteria for these disorders.The paradigm was a modified version of the visual go/no-go task, programmed using E-Prime . Stimuli were presented centrally on a color monitor positioned approximately 57 cm in front of participants. Interstimulus interval (ISI) was randomly jittered between 2.8 and 3.8 sec; stimulus duration was 100 msec. Participants were instructed to fixate on a central point and press a response button  each time a frequent “go” stimulus appeared and to refrain from responding to an infrequent “no-go” stimulus. There were 600 trials in total with 150 (25%) no-go trials, presented in three different motivational conditions . The paradigm was presented in the context of a “space” theme; go stimuli were green aliens measuring 43-mm height by 40-mm width; no-go stimuli were black aliens of equal size. Participants were encouraged to “catch” as many green aliens as possible while avoiding catching the black aliens. A time limit (reaction time [RT] cap) was imposed on go trials: participants lost 1 point for each slow or missed response  and gained 1 point for each timely response.To minimize between- and within-subject variance in inhibition rate, the RT cap was dynamically altered throughout the experiment by a tracking algorithm. Prior to the start of the experiment, participants performed a practice session comprising 20 go trials, which used a staircase procedure to identify the shortest time within which they could respond. This value became the lower bound of the tracking algorithm during the main experiment (floor RT). The initial value of the tracking algorithm for each motivational condition was set at this value plus 200 msec. This RT cap was altered dynamically, based on performance on no-go trials: following failed inhibits (FI), the cap increased by 25 msec to improve the chance of success on the next no-go trial; each successful inhibit (SI) resulted in a 25 msec decrease. There was an upper bound of 900 msec for all participants.Participants performed the go/no-go task in three different motivational conditions: baseline (low motivation); reward; and response cost. In the baseline condition, participants gained or lost 1 point following each SI or FI, respectively. In the reward condition, 5 points were given for each SI; in the response cost condition, 5 points were deducted for each FI. Thus, in the baseline condition, the value attached to inhibiting on a no-go trial was equal to that of responding quickly on a go trial. In the motivated conditions, the value attached to successfully inhibiting on a no-go trial was greater than the value attached to responding quickly on a go trial, resulting in relatively greater incentive to inhibit.Stimuli were presented in five blocks, with each motivational condition randomly presented once within each block. At the end of each condition, a visual display detailed how many points had been lost and gained for go and no-go trials. At the end of each block, instructions emphasized either the need to withhold responses to the no-go or make timely responses to the go stimulus, depending upon whether participants achieved 50% successful inhibitions during the block.Inhibition rates are presented in et al. . For the off medication session, they were required to stop taking their medication 36 hours beforehand. Group mean methylphenidate dose was 1.11 (SD = .42) mg/kg. Symptoms were assessed each time using the DuPaul et al.  ADHD-RatParticipants attended on two separate days, each consisting of an EEG session and a functional magnetic resonance imaging (fMRI) session (not reported here), with the order of testing counterbalanced and held constant across the 2 days. Attention-deficit/hyperactivity disorder participants were tested off and on medication; control subjects were never medicated but were tested twice to control for practice effects. Control (CTRL) and ADHD groups were pairwise matched on sociodemographic variables and on the order in which each pair completed EEG and fMRI testing. In between-group statistical analyses, the off-medication session of each ADHD participant was compared with the equivalent session of their matched control subject. Data from two participants in the ADHD group who did not complete the off-medication ERP session were excluded from analysis; the control participants with whom they were matched remained in the analysis to increase power.Data were collected using a Biosemi Active II System  with 128-channel montage of silver/silver chloride (Ag/AgCl) electrodes, sampled at 256 Hz. Additional electrodes were placed at the inner orbital ridge and the outer canthus of each eye to record eye movements and on each mastoid to record other artefacts. During data collection, voltage signals were referenced to an electrode placed to the left of electrode Cz.Analysis was performed using Brain Vision Analyzer (BVA) 1.05 . After removal of noisy/flat channels, data were re-referenced to the average reference and filtered using .5 Hz high-pass and 30 Hz low-pass zero-phase shift Butterworth filters with slope of 24 dB per octave. Data were segmented into epochs, 2800 msec in length, with a prestimulus period of 650 msec. Large epochs were created at this stage to improve reliability of ocular correction, conducted using a regression method . Epochs Peak detection was performed using a semiautomated procedure in which peaks were detected automatically by the BVA software and checked by an expert blind to group status, according to the following criterion: N2  at Fz and Cz; P3 (mean amplitude in a 400–700 msec time window) at Cz and Pz. The early portion of the waveform often contained a negative shift; to provide a more reliable measure of N2 amplitude, the peak was calculated as the difference in amplitude between the N2 and the preceding positive peak. The P3 was measured as mean amplitude because in the majority of datasets, the activity in this time window occurred over a long time period and it was frequently difficult to identify one specific peak.p2) are reported. Main effects and interactions significant at p < .05 (two-tailed) and trends (p < .1) were followed up with further analysis. Effects of motivation were investigated with planned Helmert contrasts comparing motivated conditions (reward and response cost) with baseline and reward with response cost.All analyses were conducted in two parts: first, effects of diagnosis were investigated by comparing the CTRL group with the ADHD group off medication. Second, effects of medication in the ADHD group were investigated by comparing the off and on medication sessions within subjects. In both analyses, motivation was a within-subjects factor with three levels . Analysis of ERP amplitudes included a within-subjects factor trial with two levels . Effect sizes  had fewer than 20 artifact-free no-go trials for ERP averaging and were excluded from analysis. Final sample sizes were 28 CTRL and 23 ADHD off medication for diagnostic analyses and 22 ADHD participants for medication analyses.The data were checked for homogeneity of variance and normal distribution. Outliers (standard deviation greater than 2.5 from group mean) were excluded. The data were checked to ensure two female subjects in the sample  were not outliers; results remained robust to exclusion of these participants. All analyses described above were rerun with IQ and ODD diagnosis included as covariates. Neither were significant predictors in any analysis; the results are reported without the covariates included.2 = 2.494, p > .1) nor session  affected these choices. Both groups more frequently chose the response cost condition  than either reward  or baseline (CTRL: 0% ADHD: 10%) as the one that made them “most careful” with no significant group  or session  effects on these choices.Participants responded to the motivational manipulations within the paradigm, choosing the reward condition  above response cost  or baseline  as the condition they “liked the most.” Neither group  < 1, ηp2 < .001] but a significant effect of motivation  with smaller mean differential in the motivated conditions (reward and response cost) than baseline (p < .001). The diagnosis × motivation interaction was nonsignificant . Analysis investigating the effects of medication and motivation on the differential revealed no effect of medication  but a significant effect of motivation , with smaller differential in the motivated conditions than baseline (p = .006). The medication × motivation interaction was nonsignificant .Data for the RT cap − floor differential are shown in Event-related potential data relevant to all statistical analyses are shown in F = 22.065, p < .001, ηp2 = .31] and a main effect of motivation  with greater amplitude for reward than response cost (p = .005). Group differences were in the predicted direction (CTRL > ADHD) but did not reach significance . The diagnosis × motivation interaction  and the diagnosis × motivation × trial interaction  were nonsignificant.Analysis revealed significantly greater amplitude on no-go than go trials , trial , and motivation  on P3 amplitude, with greater amplitude for CTRL than ADHD, for no-go than go trials, and for reward and response cost compared with baseline (p = .003). The diagnosis × motivation interaction  and the diagnosis × motivation × trial interaction  were nonsignificant.There were significant main effects of diagnosis  and for no-go than go trials . There was a main effect of motivation  with greater amplitude in motivated conditions than baseline (p = .045) and in the reward condition compared with response cost (p = .036). The medication × motivation  and medication × motivation × trial  interactions were nonsignificant.One extreme outlier was excluded. Amplitude was significantly greater on than off medication  and for no-go than go trials . There was a main effect of motivation  with greater amplitude in both motivated conditions compared with baseline (p = .007) and no significant difference between reward and response cost (p > .1). The medication × motivation  and medication × motivation × trial  interactions were nonsignificant.Amplitude was significantly greater on than off medication [This study investigated the effects of motivational incentives and medication on electrophysiological indexes of response conflict and attention in children with ADHD. To ensure neural correlates were invoked to a similar degree in all children, a tracking algorithm minimized between- and within-subject variance in the ratio of failed to successfully inhibited no-go trials. Analysis of the self-report visual analogue scales confirmed that participants responded to the motivational incentives: participants in both groups and sessions chose the reward condition as the one they liked the most and the response cost condition as the one that made them most careful. The success of the tracking algorithm and the motivational incentives was critical to assessing effects of diagnosis, medication, and motivation on the ERPs.In support of previous research, the P3, an index of attention to a task-relevant stimulus  was signWithin-subjects analysis revealed significant effects of medication on N2 and P3 amplitudes, supporting the relatively limited research in this area  and idenAlthough the sample sizes were large compared with many other ERP studies in this field , statistical power may have been insufficient to detect critical interactions. However, several methodological steps were taken to maximize power: careful matching of samples on age, gender, and SES; conducting analysis on the equivalent session for each matched CTRL-ADHD pair; tracking algorithm to reduce between-subjects variance; and careful preprocessing of EEG data. Power calculations revealed 79% power to detect an effect size of .4 and 84% power to detect an effect of .3 for the diagnosis by motivation and medication by motivation interactions, respectively. Nonsignificant interactions are therefore likely to be small. Low numbers of successfully inhibited no-go trials meant it was not possible to investigate neural correlates specific to successful inhibition. Previous studies have identified differences in the morphology of the waveform on FI and SI trials, particularly with regard to the amplitude and latency of the N2 and P3 . A numbeThis is the first study to report effects of motivation on ERP correlates of response conflict and attention in children with ADHD. Stimulant medication also increased N2 and P3 amplitude. Methylphenidate treatment and motivational incentives had independent rather than synergistic effects on these ERP markers, with relatively greater effects of medication than motivation. Future research should investigate under controlled conditions whether the additive effects reported here for motivational incentives and stimulant medication in ADHD is replicated for behavioral and symptomatic outcomes.


Bartonella spp. from exotic small mammals, we investigated the prevalence of Bartonella spp. in 546 small mammals (28 species) that had been imported into Japan as pets from Asia, North America, Europe, and the Middle and Near East. We obtained 407 Bartonella isolates and characterized them by molecular phylogenetic analysis of the citrate synthase gene, gltA. The animals examined carried 4 zoonotic Bartonella spp. that cause human endocarditis and neuroretinitis and 6 novel Bartonella spp. at a high prevalence . We conclude that exotic small mammals potentially serve as reservoirs of several zoonotic Bartonella spp.To evaluate the risk for emerging human infections caused by zoonotic  Bartonella includes a variety of gram-negative, fastidious, hemotrophic bacteria that are transmitted by blood-sucking arthropod vectors. The genus consists of 20 species and 3 subspecies; at least 11 of these species are known or suspected to be pathogenic for humans as causative agents of emerging zoonoses  examine the prevalence of Bartonella spp. infection in exotic small mammals imported into Japan from various countries, 2) compare the diversity of these Bartonella strains by analyzing the partial sequence of the citrate synthase gene (gltA), and 3) evaluate the possibility that these mammals may serve as potential reservoirs of zoonotic Bartonella spp.Many exotic animals are traded as pets around the world and have been imported into Japan without quarantine. However, no data exist on the prevalence of infection with For this study, 546 exotic small mammals were purchased from trading companies. The animals represented 3 orders and included 6 families, 23 genera, and 28 species . They ha2. After 2 weeks of incubation, 2 or 3 colonies with genus Bartonella morphologic characteristics  were picked from each plate, confirmed to be gram-negative pleomorphic bacteria, and subcultured using the same conditions used for the original cultures.The blood sample pellets were thawed at room temperature, 100-μL supplemented Medium 199 (gltA gene to confirm that the bacteria were from the genus Bartonella. PCR was performed by using an iCycler (Bio-Rad) with a 20-μL mixture containing 20 ng extracted DNA, 200 μM of each deoxynucleoside triphosphate, 1.5 mmol/L MgCl2, 0.5 U Taq DNA polymerase , and 1 pmol of each primer. The specific primer pair and PCR conditions for gltA were as previously reported . The extracted DNA was used for PCR analysis of a 312-bp part of the gltA sequences from the isolates and type strains of established Bartonella spp. in GenBank/EMBL/DDBJ were aligned with the Clustal X program . Direct DNA sequencing of the purified PCR products was carried out by using dye terminator chemistry with specific primers  from China were found to be infected with bartonellae; no bartonellae were isolated from animals in the families Petauridae, Muridae, Octodontidae, or Dipodidae.The prevalence of bartonellae in the exotic small mammals examined was 26.0% (142/546). A total of 407 isolates were obtained from the 142 bacteremic animals . The preAcomys cahirinus) to 100% (10/10) in the bushy-tailed jird . Prevelances were considerably higher for the bushy-tailed jird, large Egyptian gerbil (Gerbillus pyramidum), greater Egyptian jerboa , and lesser Egyptian jerboa (J. jaculus) at 100% (10/10), 90.0% (9/10), 81.3% (13/16), and 75.0% (6/8), respectively.Bartonellae were isolated from 17 of the 28 animal species studied . The pregltA genes. The sequence of a genotype from a Cairo spiny mouse was identical to that of the B. elizabethae type strain (GenBank accession no. Z70009) isolated from a human patient with endocarditis , which was isolated from a California ground squirrel (Spermophilusbeecheyi) and was genetically identical to an isolate from a human patient with myocarditis  and Columbian ground squirrels (Sp. columbianus), which formed a mixed clade  isolated from 7 squirrel species, was related to ed clade .Bartonella spp., and sequence similarities between genogroups B to G were also low (87.5%–93.6%). The novel Bartonella genogroups B, C, D, and E were isolated from greater Egyptian jerboas, tricolored squirrels , fat-tailed gerbils (Pachyuromys duprasi), and golden spiny mice (A. russatus), respectively. The genotypes in group F were isolated from 6 animal species: large Egyptian gerbils, fat-tailed gerbils, fat sand rats (Psammomys obesus), lesser Egyptian jerboas, greater Egyptian jerboas, and bushy-tailed jirds; those in genogroup G were isolated from a bushy-tailed jird and a large Egyptian gerbil  to the type strains of known n gerbil . In genoSciurus vulgaris subsp. orientis), and Eurasian small flying squirrels (Pteromys volans). Their sequences showed high similarity (98.4%–98.7%) to B. grahami type strain (V2) (The 2 novel genotypes (AB444993 and AB444994) in genogroup H were also isolated from Siberian chipmunks, a Hokkaido squirrel (ain (V2) .B. elizabethae type strain (F9251) ranged from 95.5% to 98.7%. The DNA sequences of gltA of the 3 isolates from a Cairo spiny mouse (AB445000) were identical to that of B. elizabethae (F9251). The sequences of the 13 isolates from lesser Egyptian jerboas were identical to those of the 16 isolates from greater Egyptian jerboas.The 10 novel genotypes in genogroup I were isolated from 9 animal species, and the sequence similarities between the genotypes (AB444995 to AB445005) and Tamiasciurus hudosonicus); it had 96.2% sequence similarity to B. clarridgeiae type strain (Houston-2), whose natural reservoir is cats  was isolated from an American red squirrel  were found to be infected with different Bartonella genogroups or genotypes  of the animals examined had bartonellae in their blood. Prevalence among wild captive animal species was high (37.3%), significantly higher (p<0.001) than that among animals from breeder facilities. Of the 179 animals (representing 9 species) from breeder facilities, only 5 Siberian chipmunks imported from a Chinese breeder were found to carry bartonellae, and these were of the same genotype as bartonellae from wild captive animals. These results suggest that animals in breeder facilities may be maintained under hygienic conditions from birth to export, so they rarely have contact with wild animals or blood-sucking arthropod vectors.B. washoensis. Kosoy et al.  were in genogroup A and showed high sequence similarity to B. grahamii–like strains in genogroup H, B. elizabethae–like strains in genogroup I, and B. clarridgeiae–like strains in genogroup J. The sequence similarities between the genotypes and the related Bartonella spp. type strains ranged from 98.4% to 98.7% for B. grahamii, from 95.5% to 95.8% for B. elizabethae, and were 96.2% for B. clarridgeiae. In humans, B. grahamii, B. elizabethae, and B. clarridgeiae have been reported to cause neuroretinitis  in Sweden  of the B. clarridgeiae–like genotype isolated in our study to that of the strain isolated from the yellow-necked mouse (AF391788) was relatively high (97.7%). Recently, B. rochalimae, a B. clarridgeiae–like organism, was isolated from a human patient with bacteremia, fever, and splenomegaly  with that of B. rochalimae strain BMGH. Studies will be required to clarify the pathogenicity of B. clarridgeiae–like organisms for humans. Such studies would include 1) evaluation of the organisms’ ability to invade human erythrocytes and/or endothelial cells, 2) demonstration of the presence and expression of the genes of type 4 secretion systems (VirB/VirD4 or Vbh) and Trw, and 3) comparisons of the entire genome sequences of the organisms and with those of other human pathogenic Bartonella spp.The sequence similarity of the Bartonella genogroups D, E, and G were isolated from animals in the family Muridae, and Bartonella genogroup B was isolated from animals in the family Dipodidae. These findings suggest strict host specificity between the strains in these genogroups and the host animal family. However, findings also showed wide host species diversity; strains in genogroup F were isolated from 6 animal species, and strains from genogroup I (B. elizabethae–like) were isolated from 9 animal species. Bartonella strains in genogroup F were isolated from animals in the families Muridae and Dipodidae. Genogroup I (B. elizabethae–like) strains were also isolated from animals in the family Sciuridae. B. elizabethae has been isolated from different animal species, e.g., a human patient and genus Rattus rats  of exotic animals were infected with different Bartonella spp. around the world. The animals in this study carried, at high prevalence, several Bartonella spp. that are human pathogens. Novel species were suggested by the fact that some of the genotypes in 6 genogroups (B to G) showed relatively low similarity (<94.6%) to known Bartonella spp. and formed independent clusters according to phylogenetic analysis based on partial gltA sequences. More taxonomic studies should sequence other housekeeping genes, such as rpoB, 16S rRNA, ftsZ, groEL, and ribC, to confirm whether these isolates are novel Bartonella spp. (Bartonella spp. carried by exotic small mammals, a quarantine system for these animals should be established as early as possible. Further studies will be necessary to clarify the route of transmission among exotic small mammals and to evaluate the pathogenicity for humans and animals of the isolates belonging to novel Bartonella genotypes found in this study.In summary, we examined the possibility that exotic small mammals may be reservoirs of zoonotic


Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe.The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated.Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated?ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group. This independent expert panel was set up to help improve the diagnosis and management of ADHD in adults throughout Europe. It is the opinion of the panel that today, due to lack of recognition and misunderstanding about the disorder and the use of appropriate, stimulant or non-stimulant medication, to control symptoms of ADHD, many adults with ADHD are misdiagnosed and are often prevented from receiving effective treatments. This may lead to unnecessary suffering for individual patients, their families and work colleagues.The European Network Adult ADHD was founded in 2003 and includes 40 professionals from 18 countries across Europe with an interest in and experience of ADHD in adults The objectives of this consensus statement are to increase awareness of the following: (1) That ADHD often presents as an impairing lifelong condition in adults, yet is currently underdiagnosed and treated in many European countries; (2) That instruments for screening and diagnosis of ADHD in adults are available; (3) That appropriate treatments exist.Three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated?This document is the result of three meetings between 2003 and 2009 in which the need for communication and a consensus statement in Europe were identified. A formally prepared document with consensus statements agreed by experts within the group was reviewed and discussed. Following this process the final document was circulated for written approval by all members of the European Network. For the assembly of the document, reviews and randomised controlled trials in adults were identified from Medline, Embase and the Cochrane Database, as well as from reviews on ADHD in children and cross-referencing and identification by the participating experts. Details of the clinical presentation of adults with ADHD were further informed by clinical expertise. This consensus statement is written for specialists in psychiatry but is also intended to increase the understanding of the disorder and to facilitate referral for diagnosis, treatment and follow-up from primary health care physicians and other health care providers.ADHD is among the most common psychiatric disorders in childhood with well established diagnostic and treatment services available throughout most of Europe. Until recently, the disorder was considered by many to resolve during adolescence and young adulthood with little or no continued impact in adult life , althougAlthough in some cases the symptoms of ADHD may appear to diminish during adolescence, this may not be the case relative to controls and does not mean that functioning is unimpaired. In a follow-up study of 119 boys of 19 years of age with childhood onset ADHD, symptom levels seemed to be lower than in childhood but 90% still did not function well . ImportaIn a study from the World Health Organisation Mental Health Survey, it was found that childhood predictors of adult ADHD included the combined subtype of ADHD in childhood, symptom severity, the presence of comorbid depression, high rates of other comorbidities, social adversity and parental psychopathology ; while BThe prevalence of ADHD in adults estimated from epidemiological studies is in the range of 2-5% -19. PersThere is growing recognition of the importance of diagnosing and treating the disorder in parents of children with ADHD  since arAnother reason for underdiagnosis and treatment of ADHD in adults is the age-dependent change in the presentation of ADHD symptoms. The more overtly impairing symptoms in childhood, hyperactivity and impulsivity, often become less obvious in adulthood, shifting the problem to more subtle symptoms such as inner restlessness, inattention, disorganisation and to impairment in behaviours related to executive functioning; and this may lead to discontinuation of treatment when they are still required ,31,35-39ADHD is an established disorder in childhood with child and adolescent mental health or paediatric services for ADHD available across most of Europe. Yet adult services for people with ADHD remain relatively scarce despite strong evidence for the benefits of diagnosing and treating ADHD in adults (reviewed in ). There Stigma related to the term ADHD is one component of the problem that nearly always arises in the context of lack of awareness or understanding of available data. Within the mental health profession stigma is further associated with the restricted regulatory status in many countries for most of the medications that treat ADHD in adults, but has other reasons as well. ADHD in adults remains a disorder which is poorly understood and where an 'emotional burden' is attached to the term especially among professionals who have not traditionally been involved in the diagnosis or treatment of ADHD ,44,45. PWhile increasing awareness and availability of accurate information is a high priority, many education programs for primary care physicians lack a component for ADHD so that a high percentage remain unaware of the way that ADHD affects people beyond the childhood years . FurtherIn terms of treatment, stimulants are by far the best studied and most effective treatment for ADHD across the lifespan, yet their use in some parts of Europe remains controversial in children and more widely across Europe in adults. The recent National Institute for Health and Clinical Excellence (NICE) guidelines from the UK describes the situation in which a drug treatment is considered safe to give to children but not safe to give to adults as an "anomaly" . The NICFamily, twin and adoption studies show that ADHD is a familial disorder with high heritability, indicating that a significant genetic component influences risk for the disorder -54. EnviFamily studies indicate a risk to first degree relatives of 4 to 10 fold the population rate, with prevalence among first degree relatives in the range of 20-50% , indicatMolecular genetic studies in adults are relatively recent but are expected to confirm some genetic associations identified in childhood ADHD samples and find other genes that relate to persistence or remission of ADHD symptoms in adult life. There is a great deal of interest in the mechanisms by which the disorder persists in some individuals and remits in others, since this may identify new targets that prevent progression of the disorder into adult life. One potential mechanism is suggested by the developmental hypothesis of Jeffrey Halperin, which proposed that ADHD is linked to an early-appearing and enduring subcortical dysfunction , while symptom remission is dependent on the extent of maturational changes in executive control ,62. The Molecular genetic studies of ADHD in children provide direct support for the association of specific genes with ADHD. Genetic variants within or near to the D4 (DRD4) and D5 (DRD5) dopamine receptor genes provide the most consistent findings supported by meta-analysis . NumerouMolecular genetic studies have also turned to the study of ADHD in adults in recent years. Much of the current research coordinated in Europe by Barbara Franke from the Netherlands for the International Multicentre Persistent ADHD Collaboration (IMPACT) group. This collaboration has successfully generated a multi-site sample of around 3,000 patients and is continuing to develop. To date several publications highlight potential associations with ADHD in adults, some but not all of which are shared with genetic association findings in children -72.Environmental factors are also associated with ADHD , particuNeurocognitive, neurophysiological and neuroimaging studies suggest that brain dysfunctions are involved in the central components of the syndrome in children and adults -82. FronThe two most frequently used diagnostic terms to describe the condition in childhood are attention-deficit/hyperactivity disorder (ADHD) and hyperkinetic disorder (HKD). For both definitions the disorder is defined as a clinical syndrome characterised by the presence of developmentally inappropriate levels of inattention, hyperactivity and impulsivity, starting in childhood and leading to impairment. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD as defined by the American Psychiatric Association are the most widely used criteria and describe three subtypes of ADHD based on the predominant symptom pattern: inattentive type, hyperactive-impulsive type and the combined type . The Inthttp://www.dsm5.org:The next edition of the DSM (version 5) now in preparation is due to be published in 2013 and the revised ICD (version 11) for 2015. The revised DSMV criteria are expected to follow similar lines to the current criteria with the following expected changes (1) Symptom thresholds: For older adolescents and adults (aged 17 and above) only 4 symptoms in either the inattentive or hyperactive-impulsive domain are required.(2) The list of hyperactive-impulsive symptoms has been increased to 13 to include 'uncomfortable doing things slowly or carefully', 'is often impatient', 'difficult to resist temptations or opportunities' and 'tends to act without thinking'.(3) Descriptions of symptom items have been elaborated to include more specific descriptions of behaviour, some of which are more applicable to adults.(4) The age of onset criteria has been broadened to include 'noticeable inattentive or hyperactive-impulsive symptoms by the age of 12 years'.(5) The requirement for clear evidence of impairment from the symptoms is a key part of the diagnostic criteria, but is no longer required before the age of 12 years or younger.(6) Autism spectrum disorder is no longer listed as an exclusion criterion.These changes recognise that impairment from the symptoms of ADHD may develop later in life and that in some cases symptoms cannot be clearly identified until the early adolescent years. The reduction in the symptom threshold for adults as compared to children recognises the age-dependent changes in the course of the disorder, since the lower threshold in adults is still clinically significant where there is clear evidence of impairment from the symptoms of ADHD; and better reflects the characteristics and natural course of the disorder. These changes mean that many people who previously met the 'in partial remission criteria' will meet full criteria for ADHD under the revised DSM-V (see below for further discussion).Whereas the core symptoms of hyperactivity, impulsivity and inattention, are well characterised in children, these symptoms may have different and more subtle expressions in adult life. Comparison with the normal behaviour of age, gender and cognitive ability matched groups must be taken into account. For instance, where children with ADHD may run and climb excessively, or have difficulty in playing or engaging quietly in leisure activities, adults with ADHD are more likely to experience inner restlessness, inability to relax, or over talkativeness. Hyperactivity may also be expressed as excessive fidgeting, the inability to sit still for long in situations when sitting is expected , or being on the go all the time. Impulsivity may be expressed as impatience, acting without thinking, spending impulsively, starting new jobs and relationships on impulse, and sensation seeking behaviours. Inattention often presents as distractibility, disorganization, being late, being bored, need for variation, difficulty making decisions, lack of overview, and sensitivity to stress. In addition, many adults with ADHD experience lifetime mood lability with frequent highs and lows, and short-fuse temper outburst ,116-118.An additional burden on family life may be the presence of one or more children with ADHD, which happens frequently due to the high familial risks of the disorder. Adults with ADHD are at risk for poorer parent-child relationships . InattenThe clinical picture of ADHD is also coloured by frequent co-morbidity. In childhood, as many as 65% of children with ADHD have one or more co-morbid conditions, including oppositional defiant and conduct disorder, anxiety and mood disorders, tics or Tourette syndrome, learning disorders and pervasive developmental disorders (e.g. autism) -147. SimAs boys dominate clinical samples of ADHD in childhood, female manifestations and gender differences have been relatively neglected in research as well as clinical practice -162. In Several factors may explain these observations. In childhood, girls may have less externalizing problems than boys: they suffer more from internalizing problems, chronic fatigue and inattention while boys may be more hyperactive and more aggressive ,166. GirAssessment starts with self-reported symptoms. The physician should perform an in depth diagnostic interview to look for the characteristic psychopathology by careful questioning about childhood and current behavioural symptoms. Although the patient appears to be the best informant, comparison with parent and partner reports in order to provide more information on severity and pervasiveness of symptoms, is desirable . Both DSWe therefore conclude that a definition of remission based on the number of criteria that have to be met in childhood does not seem appropriate in clinical practice with adults, especially as symptoms described by both DSM-IV and ICD-10 criteria typically apply to children and are not adjusted for developmental age ,172,173.Further work is now required to clarify whether broadening the criteria to include those with four or more symptoms in either domain is sufficiently specific within adult mental health populations, since by lowering the threshold other acute psychiatric disorders may generate ADHD-like symptoms that reach this lower threshold. This is however mainly a problem for cross-sectional screening for ADHD, since in clinical practice the diagnosis is based on eliciting a history of ADHD symptoms that start in childhood or early adolescence and are persistent (trait-like) and impairing over time and can therefore be differentiated from adult onset disorders. The other approach under investigation is the identification of alternative descriptions of behavioural impairments seen in adults with ADHD, such as the ecological executive function deficits described by several authors in recent years ,176, whiAs discussed, the expression of ADHD in adults is to some extent different from that in children and the diagnostic descriptions of some of the features need to be adapted to adult expressions of the disorder. For example, physical overactivity in children could be replaced in adulthood by constant mental activity, feelings of restlessness and difficulty engaging in sedentary activities. Furthermore a range of characteristics closely associated with the core ADHD syndrome often lead to some of the impairments typically seen in adults with ADHD. These include symptoms such as disorganization, short-fuse, temper, mood lability and sensitivity to stress ,116. AssAnother difference in the evaluation of ADHD in adults is the usual reliance on self-report of symptoms rather than informant accounts of behaviour by parents and teachers. Although the validity of a retrospective diagnosis of ADHD in adults may be questioned in some cases, this is also true for other psychiatric diagnoses that are dependent on descriptions of current and past behaviour. Self-reports of past and current symptoms can however be reliable if the patient has good insight into the condition . NeverthAnother important criterion to evaluate is the age of onset. The DSM-IV criterion that some symptoms and impairment should be evident before the age of 7 years is difficult to assess accurately in a retrospective diagnostic assessment in adults. In fact, research has failed to validate to this criterion since it has been found that the clinical syndrome that defines ADHD has similar clinical predictions in terms of course, treatment response and associated impairments regardless of whether symptoms with impairment started before the age of 7 years or later -187. ThiA further problem is recall bias by parents, since after decades they may not accurately recall when symptoms or impairments started. Recent evidence found that on average parents typically report a later age of onset by around 5-years, even where earlier age of onset was known from previous health care records ,189,190.For these reasons it is proposed to use a broader onset criterion, up to early to mid adolescence ,191 and In addition to the evaluation of symptoms, another important criterion for the clinical diagnosis of ADHD is the presence of significant levels of impairment associated with the symptoms. This is critical because the symptoms of ADHD are found to be continuously distributed throughout the population and there is no natural boundary between affected and unaffected individuals . As withCurrent evidence clearly defines ADHD as a clinical syndrome associated with impairments in multiple domains including academic difficulties, impaired family relationships, social difficulties and increased rates of conduct problems. In adults with ADHD increased rates of antisocial, drug use, mood and anxiety disorders are reported in both cross-sectional and longitudinal follow-up studies; in addition to increased rates of unemployment, poor work performance, lower educational performance, increased rates of traffic violations and accidents and criminal convictions: reviewed in NICE, .Finally, the high familial risk among first degree relatives, in the order of 20% or more , means tDiagnosis is based on a careful and systematic assessment of a lifetime history of symptoms and impairment. It is not just based on a single clinical impression gained during consultation. Central to this process is the assessment of childhood-onset, current symptoms of ADHD and the presence of symptoms and impairment in at least two domains . Associated features should be evaluated including mood lability, temper outbursts and comorbid disorders . It is important to take a full medical history of psychiatric and somatic treatments, as well as a family history of psychiatric and neurological problems. It is useful to ask the patient about the pattern of symptoms, typical of ADHD and its co-morbidities in his/her family, taking into account familial factors and the high heritability of the symptoms. Patterns of comorbidity in children and adults with ADHD have been identified and include: mood, anxiety, sleep, conduct and substance use disorders as well as personality disorders. Some care must be taken to distinguish between symptoms that often co-occur with the core syndrome of ADHD  from those of a separate comorbid condition . Comorbidity being the rule rather than the exception, the evaluation of co-occurring symptoms, syndromes and disorders must always be part of the clinical assessment of adult ADHD ,150.ADHD is also associated with increased rates of neurodevelopmental traits and disorders including autism spectrum disorder , dyslexiComorbid substance use disorder (SUD) deserves special attention due to the high rates of ADHD within SUD populations. A bidirectional link between ADHD and SUD is reported ,200 withAlthough there are many challenges in identifying undiagnosed ADHD in SUD settings, systematic screening is feasible . This isClose supervision is advised when treating ADHD patients with SUD with stimulants and in cases where diversion or abuse is a particular concern, atomoxetine may be selected as the first line treatment. Research in ADHD populations suggests that only a small minority divert or misuse their medication  and certhttp://www.hcp.med.harvard.edu/ncs/asrs.php[There are many screening instruments and diagnostic interviews available, some of which have been translated into different languages. Commonly used rating scales for screening include the ADHD Rating Scale, based on the DSM-IV criteria , and the/asrs.php. The ASR/asrs.php. Specifi/asrs.php.To guide the diagnostic assessment process, other self-report questionnaires are available, such as the Brown ADD Scale Diagnostic Form (BADDS)  that meaFor the main diagnostic assessment use of a structured diagnostic interview is advised, such as the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID) . An alteCurrently there are no neurobiological or neuropsychological tests for ADHD with sufficient sensitivity and specificity to serve as an individual diagnostic test . FunctioDespite the poor predictive value of cognitive performance tests, some experts conceptualise ADHD as primarily a deficit of executive functions. While this may not always be seen in cognitive performance deficits, impairments are usually seen in the way that people with ADHD manage daily tasks ,176. ManIt is important for the diagnosis of ADHD, as well as the correct targeting of treatments, to identify comorbid conditions such as mood, anxiety, psychotic, organic and substance use disorders; in addition to personality, tic and autistic spectrum disorders. Because adults with ADHD often exhibit low self-esteem, low mood, affective lability and irritability, these symptoms may sometimes be confused with dysthymia, cyclothymia or bipolar disorder and with borderline personality disorder. Furthermore daily mood changes in ADHD are very common, and represent a poorly regulated but essentially normal range of moods, rather than the more severe extremes of depression and elation seen in bipolar disorder; and it is argued that chronic mood instability should be considered part of the core syndrome of ADHD ,175,231.ADHD and borderline personality disorder seem to share impulsivity, affective instability, anger outbursts and feelings of boredom ,117,218.The symptoms of ADHD can be treated effectively in both children and adults. The beneficial effects of stimulant medication and atomoxetine on the core symptoms of ADHD have been demonstrated in numerous studies in children. An increasing number of studies in adults demonstrate a similar clinical response to that seen in children ,236-239.Long-term follow-up, epidemiological and clinical studies have shown that adults with untreated ADHD, when compared to normal controls, experience higher rates of academic failure, low occupational status, increased risk of substance use disorders , accidents and delinquency, and have fewer social relationships or friends ,243,244.• psychological functioning and self-confidence• family/relationship functioning• interpersonal (broader than family) functioning• professional/academic functioning• cognitive deficits• driving performance• risk of substance use disordersSimilar to the treatment of ADHD in children, a multimodal approach to treatment of adults with ADHD and associated co-morbid disorders should be taken . Ideally• psycho-education of ADHD and comorbid disorders• pharmacotherapy for ADHD and comorbid disorders• coaching• cognitive behaviour psychotherapy • family therapyTreatment should follow careful diagnostic assessment of ADHD and associated comorbid disorders. In the case of comorbidity, the integrated treatment plan should address both ADHD and the comorbid condition, the order of pharmacological treatment depending on the type and severity of comorbidity. Generally, severe mental health disorders should be treated first, such as in-patients with psychosis, major depression, mania or drug addiction; following which the diagnosis of ADHD and need for treatment can be reviewed. However, treatment of milder depressive and anxiety disorders may be deferred until after treatment of ADHD and often needs no further treatment as the comorbid symptoms may resolve following effective treatment of ADHD. Symptoms such as demoralisation and low self-esteem following a life with ADHD, and mood instability, improve with stimulant treatment alone . It is uWith respect to substance use disorders, ADHD is considered an important factor in its aetiology as the substances are often used for self-medication and may relieve symptoms like restlessness, inattention, impulsivity and sleep problems ,249-251;However, in some countries, regulatory rules will not allow prescription of stimulants in patients with substance use disorders. Patients should be asked to register their drug/substance intake and be encouraged to stop their use. Despite concerns that pharmacotherapy with stimulant medication may be a risk factor for substance abuse, the literature supports the view that stimulant treatment for ADHD either has no impact in risk for substance abuse, or may even lower the risk of substance abuse by reducing the early onset of substance abuse in adolescents ,257-259.Psycho-education is the first step in the treatment plan and involves educating the patient and ideally also the partner or family about ADHD symptoms and impairment, the prevalence in children and adults, the frequent comorbidity, the heritability, the brain dysfunctions involved, as well as the treatment options. In many cases, simply providing the patient with this information may help the patient's understanding and bring him or her comfort. Often this process offers new insights into past difficulties. Relationship difficulties often decline after this sharing of information with family members. Feelings of guilt and remorse can be left behind, and the patient's social network may begin to be restored. This social network will prove invaluable to the patient during the treatment process. Informing the patient about the existence of self-help groups may be valuable, allowing him or her to join and share information and experiences, as well as to gain further comfort and understanding. There is a need to further develop structured psychoeducation programs with specific objectives.Stimulants (methylphenidate and dexamphetamine) are first choice medication treatments for ADHD in children and adults, based on an extensive and still growing body of data concerning efficacy and safety ,260. AtoStimulants are effective in about 70% of patients with ADHD in controlled studies -267 depeAlthough stimulants are by far the best studied and most effective treatment for ADHD, their use in some parts of Europe is still controversial in both children and adults. It is not yet common practice for doctors to prescribe stimulant medication to adults. As a result support services and expertise for treating ADHD in adults are not always available. As discussed earlier, the use of stimulants continues to be hampered by stigma and lack of up to date information in their use, with restricted access in many European countries .The hesitancy and uncertainty about the appropriate use stimulant medication by both the general public and many physicians may also be related to the history of abuse with amphetamines in the past. Health authorities have given methylphenidate the same drug classification as amphetamines and they both perform similar to each other in traditional assays of abuse ,281. AbuImportantly, both clinical studies and clinical experience support the view that the methylphenidate does not lead to stimulant or drug addictions. On the contrary, it has been shown to have a neutral or reducing impact on substance abuse and the risk of relapse ,253,254.Continued research in adult patients and education about efficacy and safety may help to overcome these problems. The non stimulant atomoxetine may be an alternative to treatment with stimulants in substance abuse patients with ADHD, although studies showing superiority over stimulants in this difficult patient population are still lacking ,284-286.In the United States, more than ten different stimulant preparations have been developed for treatment of ADHD, the most recent being long acting formulations of oros-methylphenidate, mixed amphetamine salts, dexmethylphenidate and lis-dexamphetamine ,287,288.Extended release preparations of stimulants have durations of action between 6 to 14 hours, which may permit once-daily dosing, although an adult may still need twice daily dosing of medication for a 12-16 hour day. Currently, combinations of immediate and extended release preparations are often prescribed in adults with the aim of tailoring the dose regime to the individual requirement and medication response of each patient. Dosing schemes and maximum daily dose vary across Europe (from 0.3-1.5 mg of methylphenidate/kg/day). However, the panel recommends that the dose of stimulants in adults should be individually adjusted, based on response and tolerability. The short half life of the medications suggest that it is more practical to consider maximum dose in terms of the maximum taken at each time point, the length of the effect of each dose on the control of ADHD symptoms, and the number of doses required to provide symptom control throughout the day; rather than a maximum based only on mg/kg per day. Individual differences in the optimal dose response to stimulant medication means that the best approach is to titrate the dose for each individual, starting at a low dose and increasing to an effective dose, while keeping side effects to a minimum; and should not be determined on a mg/kg basis.In Europe, limited and different products are registered in the various countries. Some countries still only have access to immediate release methylphenidate and may or may not have access to dexamphetamine, while increasingly the longer-acting extended release preparations are being introduced. In Switzerland Dexmethylphenidate XR was licensed for use in adults in 2009 and this has been reported as a safe and effective option .For adults with ADHD who do not respond to stimulant therapy or who have a condition in which a stimulant is contraindicated, the non-stimulant atomoxetine that is licensed for child and adult ADHD in the USA is an appropriate alternative . AtomoxeIn more complicated co-morbid cases, clinical experience indicates that treatment may be combined with antidepressants and mood stabilizers, although controlled studies are still lacking . A recenPharmacotherapy alone is usually not sufficient to stabilise the many problems of adults with ADHD. Coaching provides a structured, supportive therapy, either individually or in group sessions. Coaching aims to teach problem-solving skills for identified practical problems. Due to a lifetime history of the impairment, adults with ADHD have typically not learnt practical organisational skills ,307 and A coaching program may include:• acceptance of the disorder• learning to deal with time management• learning to limit activities to 'one goal at a time'• organising home, administration, finances• dealing with relationship and work difficulties• learning to initiate and complete tasks• understanding emotional responses associated with ADHDThese components of coaching are also addressed by cognitive behavioural therapy for adult ADHD ,308. AccCurrent research does not support the efficacy of psychotherapeutic treatments as sole treatment for adult ADHD; neither do they relieve the core symptoms of ADHD. They are however considered an import adjunctive treatment for people who prefer a psychological approach or where residual symptoms or comorbidities remain. CBT has a strong evidence base for the treatment of some of the comorbidities associated with ADHD yet there are few controlled trials in adults with ADHD. The findings in ADHD are reviewed by the Research Forum on Psychological Treatments for Adults with ADHD, who identified moderate to large effect sizes from five empirical studies. They concluded that psychological treatments may play a critical role in the management of adults with ADHD who are motivated and developmentally ready to acquire new skills as symptoms remit . Safren ADHD in adults presents as a lifelong condition that started during childhood. The precise details of the clinical presentation may change with age and with the demands of adult life, but are broadly similar to those seen in children. As medication treatment for ADHD does not cure the disorder and some or all symptoms may return after discontinuation of medication, long-term pharmacological and psycho-social treatment may be necessary. The poor long term prognosis of untreated ADHD has implications for the costs of illness. In children, the economic burden of ADHD has been estimated to be approximately double those of normal controls, due to substantially more inpatient as well as outpatient hospitalisations and emergency department visits . The ecoA summary of the main conclusions is listed in Table The following co-authors have no competing interests: Dr Pierre Oswald, John Fayyad, Doris Ryffel, Karen Foeken, Pieter-Jan Carpentier, Chantal Henry, Martin D. Ohlmeier, Helmut Niederhofer, Stefano Pallanti, A. Pehlivanidis.The following co-authors have the following competing interests: Dr. J.J.S. Kooij has participated in research with and has been on the speaker bureau of Janssen-Cilag and Eli Lilly. Dr Steven Stes have served as a consultant for Novartis, received educational grants from Janssen-Cilag, conference attendance support and/or served on the speaker bureau of Janssen-Cilag, Novartis, GlaxoSmithKline and Lundbeck, served on the advisory board of Janssen-Cilag and Novartis and he is also a co-author of a book about adult ADHD that is commercially available (for patients and their environment). Dr. J. Antoni Ramos-Quiroga has received fees from Janssen-Cilag, Shire, Lilly and Rubió and funds from Janssen-Cilag, Lilly and Rubió. Dr. Miguel Casas has received fees from Janssen-Cilag, Lilly and Rubió and funds from Janssen-Cilag, Lilly and Rubió. Dr Dan Edvinsson have been a Consultant for Bristol-Myers Squibb and Novartis, a speaker for Janssen-Cilag, Novartis and Lundbeck; and participated in medical trials for Janssen-Cilag (Lambda 1+2). Dr Ylva Ginsberg has served as a consultant and speaker for Janssen-Cilag and Novartis and as a speaker for Lundbeck. She is a Principal Investigator for LAMDA 1 and LAMDA 2 funded by Janssen-Cilag. Dr Michael Fitzgerald has been a consultant for Shire and has been on the advisory board for Lilly and Janssen Cilag. Dr Michael B. Lensing has received honorarium from Janssen Cilag as member of a Scientific Committee in connection with NPA (Nordic Psychiatric Academy ADHD) meetings in 2009 & 2010. Dr Maria Råstam has acted as speaker for Eli Lilly, Jansen Cilag and Novartis. Dr Iris Manor is a consultant for Janssen-Cilag and has been Principal Investigator for Enzymotec Ltd. and Alcobra Ltd. and funded by them for this work. She has also given courses and lectures to Israeli specialists and pharmacists that were funded separately by Janssen-Cilag, Teva and Novartis. She was funded for the IMAGE study by the NIH and is a member of APSARD  and was funded for a CME about ADHD. Dr Andrew Blackwell is an employee of Cambridge Cognition Ltd. Dr Hervé CACI have in the past five years received reimbursements and/or fees from Lilly and Shire and also been an investigator or principal investigator in studies conducted by Lilly, Sanofi-Synthélabo, Janssen-Cilag and Shire. Dr Gaillac Veronique took part in the Eli Lilly atomoxetine adult study (LYDO) and a clinical study on adult ADHD sponsored by Bioproject. Philip Asherson has received speaker fees and been on advisory board meetings for Janssen, Shire and Flynn Pharma. He received an educational grant from Janssen and is principal investigator for a study funded by Shire.We thank all co-authors for their considerable expertise in generating the consensus paper. Authors all gave freely of their time for this work. All authors took part in meetings between 2003 and 2009 which formulated the content of the consensus statement. A formally prepared document with consensus statements was generated by SK and subsequently revised by PA, with the assistance of all co-authors. The entire content was reviewed by all the co-authors. Following this process the final document was circulated for written approval by all members of the European Network and further changes made on the basis of written comments and text changes.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/10/67/prepub


In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults.To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS .Phenotype data from over 12,000 adults  registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling.Heritability estimates for ADHD from the twin-family study.Heritability of ADHD in adults is estimated around 30% in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important.Heritability for ADHD features in adults is present, but is substantially lower than it is in children. It is associated with considerable social, family, behavioral and cognitive dysfunction and is comorbid with depression, bipolar disorder, anxiety, and substance use A recent study observed strong familial clustering of ADHD in first-degree relatives of adults with ADHD. Compared to a control group adults with ADHD had significantly more first-degree relatives with ADHD (28% versus 5%) In this manuscript we present a quantitative genetic study of adult ADHD in a large sample of twin families who are registered with the Netherlands Twin Register Heritability was estimated using data from twins, their parents and siblings with structural equation modeling and under different models of familial resemblance. Adding data from siblings to the classical twin design results in an increase in power to detect non-additive genetic effects The classical twin design can inform on the influence of shared environment, but is not informative with respect to how much of the environment that is shared among offspring is transmitted from parents to offspring . It is easily conceivable that growing up with a parent who scores high on a number of ADHD features influences the phenotype of their offspring. By adding phenotypic data from parents to the classical twin design, vertical cultural transmission, reflecting the non-genetic influence of the parents' ADHD features on their offspring, can be examined. Because ADHD is expected to have a heritable component, vertical cultural transmission will induce genotype-environment correlation Phenotype data were collected in participants from the Netherlands Twin Register (NTR) by survey in 2004–2005 (survey 7) and in an ongoing study (survey 8) that started in 2009. Data collection for survey 7 has been detailed in Distel et al The study was approved by the Central Ethics Committee on Research involving human subjects of the Vrije Universiteit Amsterdam, an Institutional Review Board certified by the US Office of Human Research Protections . All subjects provided written informed consent.In survey 7, the screening self-report (CAARS - S:SV) form of Conners' Adult ADHD Rating Scales (CAARS) was included that consists of 30 items accessing ADHD symptom level according to DSM-IV criteria Twin-family studies make use of the different degree of genetic relatedness of family members to estimate the relative contribution of genes and environment to the variance of a trait. Monozygotic (MZ) twins are genetically (nearly) identical. Under random mating dizygotic (DZ) twins and non-twin sibling share on average 50% of their segregating genes, while parents and offspring share exactly 50% of their autosomal genes. In quantitative genetic analyses, phenotypic variance is modeled as a function of genetic (G), shared (C), and non-shared environmental (E) influences. Genetic variance can be additive (A), indicating that the effects of alleles are additive, or non-additive  referring to the interaction among alleles. All genetic effects are shared by MZ twins. DZ twins and siblings are correlated 0.5 for their additive genetic values, as are parents and offspring. DZ twins and siblings are correlated 0.25 for their non-additive genetic values, for parents and offspring this correlation is zero. Under non-random mating the correlations among family members for additive genetic values may increase Genetic analyses were carried out using structural equation modeling in Mx 2 with degrees of freedom (df) equal to the difference in the number of parameters in the two models. If the χ2-test yields a significant p-value (e.g. lower than 0.05 or 0.01), the constrained model is deemed not significantly worse. However, the chi-squared value is inflated as the sample size increases. For this reason, big discrepancies in small samples may not be significant whereas small differences in big sized samples are significant. Given the large sample size in this study  decisions about goodness-of-fit were based on the RMSEA (Root Mean Square Error of Approximation) which is obtained as: RMSEA = √(F0/df), where F0 is the chosen fit function The standard approach to the comparison of different models is by means of likelihood-ratio tests, by subtracting the negative log likelihood (-2LL) for a more restricted model from the -2LL for a more general model. This yields a statistic that is distributed as χTest-retest data were available for 2,519 subjects who took part in NTR surveys 7 and 8. The average age was 41.18 (SD = 13.66) at the first and 45.01 (SD = 13.77) at the second assessments. The correlation between the two assessments was 0.66. There were no differences in average scores for ADHD index (7.75 (SD = 3.79) and 7.54 (SD = 3.87)) between the two assessments. The six month test -retest correlation assessed on 200 unrelated individuals who took part in survey 7 was 0.67.The estimates of means from a saturated model (corrected and uncorrected for age) are given in The pattern of familial correlations in Model comparisons  and the offspring generations (average age 34 years). In fact, the parent-offspring correlations were of similar magnitude as the sib-sib and DZ twin correlations, providing evidence that the same set of genes may be playing a role across the adult life-span.The heritability estimate in adults is substantially lower than the heritability of ADHD and Attention Problems in children. A large longitudinal study of children aged 3–12 year estimated heritability for Attention Problems at 75% at all ages The age at which heritability decreases from the high estimates in childhood to the lower estimate as reported in the current study may be somewhere during adolescence. A longitudinal study in young adult twins (18–30 years) of self-reported Attention Problems estimated its heritability at 40% The large difference between childhood and adult ADHD heritability is remarkable if we compare these results to those for IQ and cognition. ADHD tends to be associated with a lower IQ This study analyzed data from over 12,000 adult subjects. Although the large sample size offered the possibility to test for different models of genetic and cultural inheritance, a limitation of the present study is that the large sample size precluded a clinical diagnosis of the phenotype. Another limitation might be that survey studies in volunteer samples increasingly suffer from non-response. Distel et al. It has been speculated that the heritability of ADHD, especially of the persistent form, may be higher in adulthood than in childhood This study clearly established the moderate stability and heritability of ADHD in adults. It paves the way for future investigations needed to fully understand the complex architecture of ADHD, such as studies on the heterogeneity of the phenotype, genome-wide linkage and association studies in adults and investigations of the effects of genotype-environment interaction and correlation. As detailed by recent reviews and meta-analyses


The pharmaceutical formulation of a new anti-tumour agent has often been perceived as the bottleneck in anti-cancer drug development. In order to increase the speed of this essential development step, the Cancer Research Campaign (CRC), the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) agreed in 1987 to form the Joint Formulation Working Party (JFWP). The main goal of the JFWP is to facilitate the rapid progress of a new drug through pharmaceutical developmental to preclinical toxicology and subsequently to phase I clinical trial. Under the auspices of the JFWP around 50 new agents have been developed or are currently in development. In this report we present our formulation experiences since the establishment of the JFWP with a selected number of agents: aphidicolin glycinate, bryostatin 1, carmethizole, carzelesin, combretastatin A4, dabis maleate, disulphonated aluminium phthalocyanine, E.O.9, 4-hydroxyanisole, pancratistatin, rhizoxin, Springer pro-drug, SRI 62-834, temozolomide, trimelamol and V489. The approaches used and problems presented may be of general interest to scientists in related fields and those considering submitting agents for development.