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Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound's impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine's clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved.Keywords: attention-deficit hyperactivity disorder (ADHD), neurodevelopment, atomoxetine, in vivo study, altered gene expression, N-methyl-D-aspartate receptor

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority-up to 90%-of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms.

Children/adolescents with attention-deficit/hyperactivity disorder (ADHD) may have a poor or inadequate response to psychostimulants or be unable to tolerate their side-effects; furthermore, stimulants may be inappropriate because of co-existing conditions. Only one non-stimulant ADHD pharmacotherapy, the noradrenaline transporter inhibitor atomoxetine, is currently approved for use in Europe. We review recent advances in understanding of the pathophysiology of ADHD with a focus on the roles of catecholamine receptors in context of the α2A-adrenergic receptor agonist guanfacine extended release (GXR), a new non-stimulant treatment option in Europe. Neuroimaging studies of children/adolescents with ADHD show impaired brain maturation, and structural and functional anomalies in brain regions and networks. Neurobiological studies in ADHD and medication response patterns support involvement of monoaminergic neurotransmitters (primarily dopamine and noradrenaline). Guanfacine is a selective α2A-adrenergic receptor agonist that has been shown to improve prefrontal cortical cognitive function, including working memory. The hypothesized mode of action of guanfacine centres on direct stimulation of post-synaptic α2A-adrenergic receptors to enhance noradrenaline neurotransmission. Preclinical data suggest that guanfacine also influences dendritic spine growth and maturation. Clinical trials have demonstrated the efficacy of GXR in ADHD, and it is approved as monotherapy or adjunctive therapy to stimulants in Canada and the USA (for children and adolescents). GXR was approved recently in Europe for the treatment of ADHD in children and adolescents for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. GXR may provide particular benefit for children/adolescents who have specific co-morbidities such as chronic tic disorders or oppositional defiant disorder (or oppositional symptoms) that have failed to respond to first-line treatment options.

Nonsuicidal self-injury (NSSI) has a high prevalence among the general undergraduate population, but as yet, no study has investigated the rate of NSSI among medical students despite the high levels of depression and suicidal ideation found in this population. Our study aimed to estimate the prevalence of NSSI and suicide attempts in German medical students and explore the associations between these behaviors and the five major personality traits. Seven hundred fourteen medical students (67% women; age range, 18-35 years; mean age, 23.1 years) participated in an online survey. We report a lifetime prevalence of 14.3% for NSSI and 1.5% for suicide attempt. The students with NSSI showed higher levels of neuroticism and openness to experience but lower levels of conscientiousness and extraversion on the NEO Five-Factor Inventory. Our results are in line with previous research from other countries regarding the prevalence of NSSI among students and its association with personality.

The classification of tic disorders has been revised in the new fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The previously expressed suggestion to categorize tic disorders within the "Anxiety and Obsessive Compulsive Disorders" was not implemented. The section "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence" was revised and renamed as "Neurodevelopmental Disorders." Tic disorders are classified there as movement disorders. Most of the changes are distinct improvements from both a clinical and a scientific perspective. For example, by removing the adjective "stereotype," the definition of tics is more precise and unified. Also, the new time-oriented criteria are more practical in the clinical setting, e.g., the exclusion criterion of a tic-free interval more than 3 months given for chronic tic disorders has been deleted. The renamings from "Transient" to "Provisional Tic Disorder" as well as from "Chronic" to "Persistent Tic Disorder" are welcome changes from a clinical perspective. Overall, the revision of the criteria is an important step towards providing more clarity and feasibility. However, the revised classification of tic disorders is still based only on clinical experience and not on evidence. Future studies should show whether the revised and improved criteria truly provide the optimal classification.

A major pathophysiological role for the dopaminergic system in Tourette's syndrome (TS) has been presumed ever since the discovery that dopamine-receptor antagonists can alleviate tics. Especially recent molecular genetic studies, functional imaging studies, and some rare postmortem studies have given more and more hints that other neurotransmitter systems are involved as well. Dysfunction in the dopamine metabolism-in particular during early development-might lead to counter-regulations in the other systems or vice versa. This chapter will give an overview of the studies that prove the involvement of other neurotransmitter systems such as the major monoaminergic neurotransmitters norepinephrine, serotonin, and histamine; the most important excitatory neurotransmitter, the amino acid glutamate; the major inhibitory neurotransmitter y-aminobutyric acid, as well as acetylcholine, endocannabinoid, corticoid; and others. These studies will hopefully lead to fundamental advances in the psychopharmacological treatment of TS. While tic disorders have been previously treated mainly with dopamine antagonists, some authors already favor alpha-agonists. Clinical trials with glutamate agonists and antagonists and compounds influencing the histaminergic system are currently being conducted. Since the different neurotransmitter systems consist of several receptor subtypes which might mediate different effects on locomotor activity, patients with TS may respond differentially to selective agonists or antagonists. Effects of agonistic or antagonistic compounds on tic symptoms might also be dose dependent. Further studies will lead to a broader spectrum of psychopharmacological treatment options in TS., (© 2013 Elsevier Inc. All rights reserved.)

Background: Tourette syndrome is a combined motor and vocal tic disorder that begins in childhood and takes a chronic course. It arises in about 1% of all children, with highly varying severity. Transient and usually mild tics are seen in as many as 15% of all children in elementary school. The diagnosis is often delayed by several years., Methods: We selectively reviewed the pertinent literature, including the guidelines of the European Society for the Study of Tourette Syndrome for the diagnosis and treatment of tic disorders., Results: Tic disorders usually take a benign course, with spontaneous improvement in adolescence in about 90% of patients. Psychoeducation is the basis of treatment in each case and almost always brings marked emotional relief. Specific treatment is needed only for more severe tics and those that cause evident psychosocial impairment. 80-90% of patients with Tourette syndrome have comorbidities (attention deficit-hyperactivity disorder, obsessive-compulsive disorder, depression, anxiety, emotional dysregulation, autoaggression), which often impair their quality of life more than the tics do and therefore become the main target of treatment. There is little evidence for the efficacy of treatment for tics. Small-scale controlled studies with a brief follow-up period have been carried out for some neuroleptic drugs. Behavior therapy should be tried before drug treatment. A further option for very severely affected adults is deep brain stimulation., Conclusion: Because of the low level of the available evidence, no definitive recommendations can be made for the treatment of tics.

Emotion-regulation difficulties have been identified as one of the core components in Non-suicidal self-injury (NSSI), a behaviour often beginning in adolescence. This pilot study evaluated differences in emotion processing between 18 female adolescents with and without NSSI by using verbal responses and functional magnetic resonance imaging (fMRI). Responses to pictures taken from the International Affective Picture System and slides with reference to NSSI were recorded both by verbal rating of valence and arousal and by fMRI. The NSSI group rated pictures with self-injurious reference as significantly more arousing than controls. For emotional pictures, the NSSI group showed a significantly stronger brain response in the amygdala, hippocampus and anterior cingulate cortex bilaterally. Depression explained differences between groups in the limbic area. Furthermore, the NSSI group also showed increased activity in the middle orbitofrontal cortex, and inferior and middle frontal cortex when viewing NSSI picture material. Participants with NSSI showed decreased activity in correlation to arousal in the occipital cortex and to valence in inferior frontal cortex when watching emotional pictures. The fMRI data support the notion that individuals with NSSI show an altered neural pattern for emotional and NSSI pictures. Behavioural data highlight proneness to excitement regarding NSSI topics. This fMRI study provides evidence for emotion-regulation deficits in the developing brain of adolescents with NSSI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Information about therapeutic serum levels of fluoxetine (FLX) and its major metabolite norfluoxetine (NORFLX) in children and adolescents is scarce., Methods: Therapeutic drug monitoring (TDM) of FLX was routinely performed in 71 subjects treated for a major depressive disorder (MDD) (10-60 mg/d FLX, median: 20 mg/d). Correlations between serum concentration and dosage, age, gender, smoking habits and adverse events were analysed., Results: Serum concentrations of the active moiety (FLX + NORFLX) ranged from 21 to 613 ng/mL (mean concentration of 213 ± 118 ng/mL, median: 185 ng/mL). High inter-individual variability in serum concentrations of the active moiety of FLX at each dosage level was observed and no relationship between serum concentration and clinical outcome was found. Apart from smoking, none of the factors tested had a significant eff ect on the serum concentration., Discussion: It was shown that serum concentrations of the active moiety of FLX in children and adolescents seem to be similar to those in adults, with a high level of inter-individual variation. The proportion of patients who showed benefits from treatment with a dose of 20 mg/d FLX was high., (© Georg Thieme Verlag KG Stuttgart · New York.)

Tourette's syndrome (TS) is characterised by motor and vocal tics. The clinical manifestation during childhood and the frequent remission during early adulthood point to a dysregulation in the maturation of neuronal pathways. As a neurobiological correlate, the cortico-striato-thalamo-cortical circuit is the main focus of research. Two main features of a movement, the speed and direction of a movement, are controlled by the basal ganglia. Both features are dysregulated in TS.  Besides the motor symptoms, patients with TS suffer from comorbidities such as attention deficit hyperactivity syndrome, depression and obsessive compulsive disorders. Tics are modified in frequency and intensity by actions that require a high level of concentration such as reading or by distress, e.g., teasing by peers. The results of structural and functional imaging data support the hypothesis of altered signal transmission in the basal ganglia and a dysfunction in the limbic system. They also point to a complex interaction between cortical motor areas, the anterior cingulum, prefrontal regions and the basal ganglia., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Endovascular treatment of intracranial aneurysms employing endosaccular coiling can be associated with aneurysm perforation, coil herniation or incomplete obliteration fueling the interest to investigate novel endovascular techniques. We aimed to test a novel embolization material in experimental aneurysms in vitro and in vivo whereby intra-arterially administered magnetic microparticles (MMPs) are navigated into the lumen of vascular aneurysms with assistance from an external magnetic field., Methods: MMPs are core-shell particles suspended in saline that have a shell made of a polymeric material and a core made of magnetite (Fe3O4). They have a diameter of 1.4 μm. During MMP administration via a microcatheter, a magnetic field was applied externally to direct the particles with the use of a solid-state neodymium magnet. Experiments were performed in a perfused silicone vessel and aneurysm model to evaluate application techniques and fluid dynamics and in the elastase aneurysm model in rabbits to evaluate in vivo compatibility, including multiorgan histological examinations and long-term stability of aneurysm embolization., Results: It was possible to steer and hold the MMPs within the aneurismal cavity where they occluded the lumen progressively. After removal of the external magnetic field, the results remained stable in vivo for the remainder of the observational period (30 minutes); after a 12-week observational period, recanalization of the aneurysm occurred., Conclusion: MMPs can be magnetically directed into aneurysms, allowing short-term obliteration. Although the method has yet to show reliable long-term stability, these experiments provide proof of concept, encouraging further investigation of intravascular magnetic compounds.

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of Tourette Syndrome (TS). The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members. Detailed clinical assessment guidelines of tic disorders and their comorbidities in both children and adults are presented. Screening methods that might be helpful and necessary for specialists' differential diagnosis process are suggested in order to further analyse cognitive abilities, emotional functions and motor skills. Besides clinical interviews and physical examination, additional specific tools (questionnaires, checklists and neuropsychological tests) are recommended.

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

Objectives: Recent studies indicate that the selective serotonin reuptake inhibitor (SSRI) fluoxetine is not solely effective by the instant inhibition of the serotonin transporter (SERT) but also by its influence on mitotic and/or apoptotic processes., Methods: To investigate the effects of the compound in vitro, we treated neurons from different brain areas with increasing concentrations of fluoxetine. Additionally, human embryonic kidney (HEK-293) cells and HEK-293 cells stably expressing the SERT were used. Cell viability was quantified by MTT-assay and apoptosis via fluorescence-activated cell-sorting analyses. Fluoxetine's effect on the γ-aminobutyric acid (GABA) receptor was electrophysiologically investigated to test the hypothesis if a GABA-mimetic effect exists that might lead - additionally to the well-known N-methyl-D-aspartate (NMDA)-antagonism - to increased apoptosis in immature neurons., Results: In hippocampal, cortical, and both types of HEK-293 cells, viability decreased and apoptosis increased in a dose-dependent manner (0.5-75 μM). In contrast, in mesencephalic and striatal cells the viability was unchanged or even slightly stimulated up to 20 μM fluoxetine. An anti-apoptotic effect of concentrations below 10 μM was observed in these cells. The GABA(A) receptor was directly activated by fluoxetine., Conclusions: We conclude that fluoxetine affects apoptotic processes independently from SERT expression. Since especially the combined GABA-mimetic and NMDA-antagonistic effects increase apoptosis in developing neuronal cells, whereas both effects are neuroprotective in adult neurons we hypothesise that these mechanisms explain the discrepancy of in vitro and in vivo studies.

Background and Purpose: There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non-stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro., Experimental Approach: The whole-cell configuration of the patch-clamp technique was used to analyse the effect of atomoxetine on N-methyl-d-aspartate (NMDA) receptors in cultured rodent cortical and hippocampal neurons as well as on NMDA receptors heterologously expressed in human TsA cells., Key Results: Atomoxetine blocked NMDA-induced membrane currents. Half-maximal inhibition emerged at about 3 microM which is in the range of clinically relevant concentrations found in plasma of patients treated with this drug. The inhibition was voltage-dependent, indicating an open-channel blocking mechanism. Furthermore, the inhibitory potency of atomoxetine did not vary when measured on NMDA receptors from different brain regions or with different subunit compositions., Conclusions and Implications: The effective NMDA receptor antagonism by atomoxetine at low micromolar concentrations may be relevant to its clinical effects in the treatment of ADHD. Our data provide further evidence that altered glutamatergic transmission might play a role in ADHD pathophysiology.

Objective: Research on psychopharmacological treatment in children and adolescents is the subject of ongoing ethical discussion, as minors with mental disorders constitute a vulnerable patient group. Considering the important legislative changes in pediatric research over the past decade in both the US and Western Europe, there is a need to review recent developments in this area., Method: Based on a systematic literature review, a hermeneutical analysis focusing the main issues of ethics in child and adolescent psychopharmacology is provided. Legal and regulatory aspects of psychopharmacological research in children are compared between the US and Europe. Relevant issues were informed assent and consent to research participation, minimal risk and burden of research, ethics of pharmacogenetics, research on "me-too" medications, and justice in global research. Additionally, the concern about undue influence of financial interests in research is also addressed., Conclusion: Incentives for the conduct of clinical trials with children comparable to those contained in US legislation are now provided in the EU. Research to develop "me-too" preparations may have no significant benefit for children, but can cause research burden and detract from clinically more important projects by utilizing limited investigator time and patient resources. Thus far, pharmacogenetic studies may bring more individualized treatment approaches into child psychiatry but they remain at present a promise for the future. Finally, the issues of avoiding undue influence from funders and conflicts of interest remain a prominent concern which can be solved by declaring conflicts and publishing all results of studies extensively.

Attention Deficit Hyperactivity Disorder (ADHD) is not only a childhood disorder but symptoms persist into adolescence and adulthood in approximately one third of the patients. Especially inattention and poor concentration impair driving performance in road traffic. Adolescents and young adults with ADHD are twice as likely to be involved in traffic accidents as people of the same age. This review sums up the legal situation in Germany and provides an overview of the current existing experimental studies on driving performance of adolescents and young adults with ADHD. Psychostimulant therapy seems to improve driving performance in ADHD patients. At the same time psychostimulants are prohibited, according to the road traffic act. Atomoxetine as a non-stimulant is not mentioned there. Therefore it could be unproblematically prescribed, however, the evidence for improved driving is not as unequivocal as for methylphenidate. The psychoeducation of adolescents and young adults with ADHD concerning their increased risk in road traffic often seems to be insufficient in clinical practice. Given the high number of traffic deaths in these young age groups consulting regarding this matter should be of high priority.

Attention-deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in youth. About a third to one-half of the affected subjects continue to have symptoms in adulthood. Remarkably, the prevalence numbers published for adult females are higher than for girls. The differences in the epidemiological data between the age groups clearly point to underdiagnosed ADHD in girls. Major depression, the most frequent psychiatric condition worldwide in adulthood, is twice as common in female as in male adults. Anxiety and depression are also among the most common comorbidities in adults with ADHD. Therefore, an undiagnosed ADHD may often underlie the psychopathology in depressive women. Another possibly associated phenomenon is the increased frequency of smoking in adult females. Since nicotine indirectly enhances the intrasynaptic dopamine level which presumably is too low both in ADHD and in depression, smoking might be used as a self-medication in women with untreated ADHD and consecutive depression. Furthermore, smoking during pregnancy is a major risk factor for ADHD in the offspring, so the vicious circle is complete. Depression in mothers of children with ADHD is associated with a higher rate of comorbidity in the children. Improved screening for ADHD in girls and treatment in childhood might thus reduce the rate of depression and smoking in adult females. We hypothesize that earlier identification and interventions might not only improve the lives of millions of girls and women but might also reduce the prevalence rates in future generations or at least moderate the deviant behaviour in this highly heritable disorder in which the development and severity of symptoms and the functional impairment depend to a high degree on epigenetic factors.

The dopaminergic system plays a key role in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate (MP), a dopamine (DA) reuptake inhibitor, is a drug of first choice for treating ADHD. This cross-over study investigated alterations in DA metabolism in young males with ADHD who had never been pharmacologically treated and MP-treated patients in comparison to healthy subjects. Dynamic 3,4-dihdroxy-6-[18F]fluorophenyl-L-alanine (FDOPA) PET scans were carried out on 20 male patients with ADHD and 18 healthy men. Eight ADHD patients had never been treated with psychostimulants, the rest had received MP. Based on the tissue-slope-intercept plot parametric images of FDOPA influx rate constant (Ki) were generated for each subject from dynamic 3D FDOPA datasets and transformed into standard stereotactic space. First a volume of interest analysis was performed on each single subject. In a second step data were introduced to a SPM2 analysis to detect significant changes in mean voxel Ki values between the normal control group and each patient group. In comparison to controls, ADHD patients as a group (irrespective of treatment status) showed a lower Ki in bilateral putamen, amygdala and dorsal midbrain. There was a lower Ki in the left putamen, right amygdala and right dorsal midbrain in untreated patients compared to controls together with a relative higher influx in the left amygdala and right anterior cingulate cortex. In contrast, methylphenidate treatment was associated with a significantly lower Ki in the striatum and amygdala bilaterally, and in the right dorsal midbrain. Untreated young adult ADHD patients showed a dopamine dysfunction that might be partly due to compensatory mechanisms. MP seems to down-regulate dopamine turnover. This effect might be one component in the mechanism of action of this drug in ADHD treatment.

Recent studies have shown that changes in the basal ganglia circuitry and limbic loops may play an important role both in Tourette syndrome (TS) and attention-deficit-hyperactivity disorder (ADHD). This study aimed to investigate in vivo possible morphological alterations of the amygdala as a key component of the limbic system. Amygdalar and total brain volumes were measured in three-dimensional magnetic resonance imaging data sets of 17 male patients with TS (mean age 11 y 8 mo [SD 2 y]; range 9-16 y) and 17 age-matched comparison children (mean age 12 y 6 mo (SD 2 y 1 mo); range 9-17 y) by volume-of-interest-based volumetry. Eight members of the TS group also fulfilled the diagnostic criteria for ADHD. A significant decrease in the left-hemispheric amygdalar volumes and in the proportions of amygdalar to total brain volumes was observed in members of the TS group compared with the comparison group. Amygdalar volumes did not correlate with tic severity, but with behavioural impairment and especially with symptoms of ADHD. The amygdalar volume reduction might be the pathoanatomical correlate of an impaired input of the amygdala to the striatum and frontal cortex. Future studies should investigate if the involvement of the amygdala is due to TS or rather caused by the genetically-linked most frequent comorbidity ADHD.

Attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioural disorder and amyotrophic lateral sclerosis (ALS), the most common adult motoneuron disease, may be two distinct entities on first sight. This paper aims to highlight parallels concerning clinical features and neurobiology. The presence of increased physical and psychological activity and largely non-progressive frontal dysfunction associated with impaired executive control and decreased attention are characteristic clinical features of both, ADHD and ALS. At the neurobiological level, there is evidence for hyperactivity in the glutamatergic system and a - potentially related - dopaminergic hypoactivity in ADHD and ALS. The clinical features of ALS resembling ADHD are particularly characteristic for the premorbid stage of the patient. Therefore, we hypothesize that clinical features of ADHD may be a risk factor for the development of ALS. This hypothesis is currently of unknown pathogenetic, but of potential future therapeutic relevance. Our hypothesis of a link between ADHD and ALS could also be considered as an example how research on neurodevelopmental diseases might influence the understanding and possibly the prevention and treatment of neurodegenerative diseases.

Methylphenidate (MPH) is the most common used drug in child and adolescent psychiatry. Despite of this fact, however, little is known about its exact pharmacological mechanisms. Here we investigated the toxic effects of MPH in vitro in human embryonic kidney (HEK-293) cells stably expressing the human dopamine transporter (HEK-hDAT cells) and in cultured rat embryonic (E14.5) mesencephalic cultures. MPH alone (up to 1 mM) affected neither the growth of HEK-hDAT cells nor the survival of dopaminergic (DA) neurons in primary cultures after treatment up to 72 h. No differences in neuronal arborisation or in the density of synapses were detected. 1-methyl-4-phenylpyridinium (MPP(+)) showed no toxic effect in HEK-293 cells, but had significant toxic effects in HEK-hDAT cells and DA neurons. MPH (1 microM - 1 mM) dose-dependently reduced this cytotoxicity in HEK-hDAT cells and primary mesencephalic DA neurons. The presented results show that application of MPH alone does not have any toxic effect on DA cells in vitro. The neurotoxic effects of MPP(+) could be significantly reduced by co-application of MPH, an effect that is most likely explained by MPH blocking the DAT.

The genesis of Tourette syndrome is still unknown, but a core role for the pathways of cortico-striatal-thalamic-cortical circuitry (CSTC) is supposed. Volume-rendering magnetic resonance imaging data-sets were analysed in 14 boys with Tourette syndrome and 15 age-matched controls using optimised voxel-based morphometry. Locally increased grey-matter volumes (corrected P < 0.001) were found bilaterally in the ventral putamen. Regional decreases in grey matter were observed in the left hippocampal gyrus. This unbiased analysis confirmed an association between striatal abnormalities and Tourette syndrome, and the hippocampal volume alterations indicate an involvement of temporolimbic pathways of the CSTC in the syndrome.