European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment.

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Can neurophysiological markers of anticipation and attention predict ADHD severity and neurofeedback outcomes?

Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited. METHODS: We analyzed children's preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity. RESULTS: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome. CONCLUSION: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.

Yes, I can - maybe Effects of placebo-related instructions on neuroregulation in children with ADHD.

Neurofeedback training (NFT) provides strategies for children with ADHD to achieve changes on the neurophysiological and behavioral level to attenuate ADHD symptoms. We assume self-efficacy (an "active attitude"), a core variable in successful NFT. In a randomized, double-blind controlled study, we investigated the impact of a "placebo instruction" on the EEG-regulation performance during two sessions of Theta-Beta-NFT in children with ADHD (age 8-12 years). Children receiving the information "this might be a placebo-training" showed inferior neuroregulation (n = 10) compared to children receiving a standard instruction (n = 12). Results of our pilot study are discussed in view of factors necessary for a valid training (ensuring maximal self-efficacy in the participants) and the fidelity of placebo-controlled trials in NFT-research.

Effects of neurofeedback on the dysregulation profile in children with ADHD: SCP NF meets SDQ-DP - a retrospective analysis.

BACKGROUND: As children with attention-deficit/hyperactivity disorder (ADHD) usually show psychopathological signs beyond their core symptoms (e.g. elevated scores of the dysregulation profile (DP) in 30-40%), treatments with a broader approach to self-regulation skills may be supportive. Neurofeedback (NF) may reflect such an option. Aim of the present analysis was to compare the effects of slow cortical potential (SCP) NF and θ/ß NF on the DP using data from a previous trial. METHODS: Thirty children with ADHD (aged 8-12 years) and a DP score in the Strengths and Difficulties Questionnaire (SDQ-DP) ⩾ 3 were included. NF treatment consisted of one block of SCP NF and one block of θ/ß NF (18 units per block) allowing an intraindividual comparison. Effects of the NF protocols were also contrasted to a control group (n = 18) that completed an attention skills training (between-group analysis). RESULTS: Regarding the SDQ-DP, SCP NF was superior to θ/ß NF and the control condition. Effects of SCP NF and θ/ß NF on ADHD symptom severity were not significantly different. The SDQ-DP score did not correlate with EEG-related measures previously found to be predictors for SCP NF on ADHD symptoms. CONCLUSIONS: SCP NF may reflect a more general approach to improve cognitive, emotional and behavioral self-regulation skills. If confirmed in a larger sample, the SDQ-DP score could be used as an indication criterion and contribute to the individualization of NF in ADHD. Overall, the differential effect provides further evidence for the specificity of NF effects.

Ginkgo biloba extract EGb 761® in children with ADHD.

OBJECTIVES: The side effects, nonresponse, and prejudices against conventional pharmacological treatments call for complementary or alternative medical treatments (CAM) for ADHD. One possible treatment, at least for cognitive problems, might be the administration of Ginkgo biloba, though evidence is currently rare. This study tests the clinical efficacy of a Ginkgo biloba special extract (EGb 761®) and its correlation with brain electrical activity in children with ADHD combined type according to DSM-IV. METHOD: In this open clinical pilot study, EGb 761® was administered to 20 children with ADHD over 3 to 5 weeks. Dosage was increased to a maximum of 240 mg daily if attention problems persisted. Possible drug side effects were assessed using the Side Effect Rating Scale. Efficacy was assessed in a multilevel approach including clinical assessment, quality of life (QoL), as well as performance and preparatory brain-electrical activity evoked during a Continuous Performance Test (Cue-CNV in the CPT). RESULTS: A very low rate of mild adverse effects occurred during the observation period. Following EGb 761® administration, possible improvements in QoL, ADHD core symptoms as well as CPT performance were detected. Improved core symptoms were positively related to elevated CNV amplitude. CONCLUSION: This preliminary evidence suggests that EGb 761® at a maximal dosage of 240 mg daily might be a clinically useful alternative treatment for children with ADHD, but further evidence is required before firm conclusions can be made.

Neurofeedback in ADHD: further pieces of the puzzle.

Among the different neuromodulation techniques, neurofeedback (NF) is gaining increasing interest in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). In this article, a methodological framework is summarised considering the training as a neuro-behavioural treatment. Randomised controlled trials are selectively reviewed. Results from two smaller-scale studies are presented with the first study comprising a tomographic analysis over the course of a slow cortical potential (SCP) training and a correlational analysis of regulation skills and clinical outcome in children with ADHD. In the second study, ADHD-related behaviour was studied in children with tic disorder who either conducted a SCP training or a theta/low-beta (12-15 Hz) training (single-blind, randomised design). Both studies provide further evidence for the specificity of NF effects in ADHD. Based on these findings, a refined model of the mechanisms contributing to the efficacy of SCP training is developed. Despite a number of open questions concerning core mechanisms, moderators and mediators, NF (theta/beta and SCP) training seems to be on its way to become a valuable and ethically acceptable module in the treatment of children with ADHD.

Chronic fluoxetine treatment changes S100B expression during postnatal rat brain development.

BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, is approved for treatment of childhood depression. In rats, fluoxetine influences neuronal development, but it is unclear whether it also influences glia development. S100B is a glia-derived calcium-binding protein, which may influence the development of serotonergic fibers and, vice versa, serotonin may influence the expression of S100B. OBJECTIVES: The purpose of this study was to investigate whether fluoxetine treatment influences the expression of S100B during postnatal development, and whether potential changes are regionally dependent upon the time frame of drug administration. METHODS: S100B gene expression and S100B protein expression in three different brain regions (frontal cortex, hippocampus, and striatum) were studied by real-time polymerase chain reaction (PCR) and immunohistochemistry, respectively. First, a short-term effect, 24 hours after a 14 day fluoxetine treatment (5 mg/kg/bw s.c.) of rats either from postnatal day (PD) 1 to 15, 21 to 35, or 50 to 64, was investigated. Then, the same treatment was used to analyze S100B gene and protein levels at PD 90 (long-term effect). RESULTS: At PD 90, a significant increase of gene and protein expression was observed in all regions if rats were treated during PDs 21-35, whereas treatment during other periods had no long-term effects. A short-term effect 24 hours after fluoxetine treatment was found for almost all development stages and regions, demonstrated by a significant increase of S100B. CONCLUSIONS: These results support recent research indicating a highly drug-sensitive period (i.e., periadolescence) of rat brain development. Therefore, further clinical studies should be performed to clarify whether such a sensitive period also exists in children.

Updates on treatment of attention-deficit/hyperactivity disorder: facts, comments, and ethical considerations.

OPINION STATEMENT: Within the last 2 years the bulk of information on evidence based treatments in ADHD was reviewed quite intensively and new empirical studies could be added. This update reports comprehensively about actual and essential facts in the field related to brain development and sensitive periods, predictors of treatment, safety of medication, value of naturalistic studies, new drugs and complementary medicine, behavioral interventions including neurofeedback and psychosocial treatment, treatment of comorbidity, and ethical considerations including preventive aspects. The updated combination of well selected evidence based treatments (ie, pharma plus non-pharma) seems to be clinically and ethically recommended as also suggested by the European and American guidelines on ADHD.

Neurofeedback in children with ADHD: validation and challenges.

Neurofeedback (NF), a type of neurobehavioral training, has gained increasing attention in recent years, especially concerning the treatment of children with ADHD. Promising results have emerged from recent randomized controlled studies, and thus, NF is on its way to becoming a valuable addition to the multimodal treatment of ADHD. In this review, we summarize the randomized controlled trials in children with ADHD that have been published within the last 5 years and discuss issues such as the efficacy and specificity of effects, treatment fidelity and problems inherent in placebo-controlled trials of NF. Directions for future NF research are outlined, which should further address specificity and help to determine moderators and mediators to optimize and individualize NF training. Furthermore, we describe methodological (tomographic NF) and technical ('tele-NF') developments that may also contribute to further improvements in treatment outcome.

[The usage of neurofeedback in children with ADHD: the method and its evaluation]. / Neurofeedback bei Kindern mit ADHS--methodische Grundlagen und wissenschaftliche Evaluation.

Neurofeedback is a computer-based behavior training, which is gaining increasing interest in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). This article gives an introduction to neurofeedback and summarizes the state of research, discussing inter alia methodical aspects (e. g., requirements to a control training). Evaluation studies conducted so far indicate clinical efficacy. For example, neurofeedback training was superior to a computerized attention training in a randomized controlled trial (medium effect size). Follow-up investigations suggest that treatment effects remain stable (at least six months). At the clinical level, comparable improvements could be obtained for the neurofeedback protocols theta/beta training and training of slow cortical potentials. Neurophysiological findings document different mechanisms of theta/beta training and slow cortical potential training. Future studies should further elucidate the specificity of training effects related to the kind of training and certain disorders and address how to optimize and individualize neurofeedback training.

Neurofeedback in children with ADHD: specific event-related potential findings of a randomized controlled trial.

OBJECTIVE: In a randomized controlled trial, we could demonstrate clinical efficacy of neurofeedback (NF) training for children with ADHD (Gevensleben et al., 2009a). The present investigation aimed at learning more about the neuronal mechanisms of NF training. METHODS: Children with ADHD either completed a NF training or a computerized attention skills training (ratio 3:2). NF training consisted of one block of theta/beta training and one block of slow cortical potential (SCP) training, each comprising 18 training units. At three times (pre-training, between the two training blocks and at post-training), event-related potentials (ERP) were recorded during the Attention Network Test. ERP analysis focused on the P3, reflecting inter alia attentional resources for stimulus evaluation, and the contingent negative variation (CNV), primarily related to cognitive preparation. RESULTS: After NF training, an increase of the CNV in cue trials could be observed, which was specific for the SCP training. A larger pre-training CNV was associated with a larger reduction of ADHD symptomatology for SCP training. CONCLUSIONS: CNV effects reflect neuronal circuits underlying resource allocation during cognitive preparation. These distinct ERP effects are closely related to a successful NF training in children with ADHD. In future studies, neurophysiological recordings could help to optimize and individualize NF training. SIGNIFICANCE: The findings contribute to a better understanding of the mechanisms underlying NF training in children with ADHD.

Neurofeedback training in children with ADHD: 6-month follow-up of a randomised controlled trial.

Neurofeedback (NF) could help to improve attentional and self-management capabilities in children with attention-deficit/hyperactivity disorder (ADHD). In a randomised controlled trial, NF training was found to be superior to a computerised attention skills training (AST) (Gevensleben et al. in J Child Psychol Psychiatry 50(7):780-789, 2009). In the present paper, treatment effects at 6-month follow-up were studied. 94 children with ADHD, aged 8-12 years, completed either 36 sessions of NF training (n = 59) or a computerised AST (n = 35). Pre-training, post-training and follow-up assessment encompassed several behaviour rating scales (e.g., the German ADHD rating scale, FBB-HKS) completed by parents. Follow-up information was analysed in 61 children (ca. 65%) on a per-protocol basis. 17 children (of 33 dropouts) had started a medication after the end of the training or early in the follow-up period. Improvements in the NF group (n = 38) at follow-up were superior to those of the control group (n = 23) and comparable to the effects at the end of the training. For the FBB-HKS total score (primary outcome measure), a medium effect size of 0.71 was obtained at follow-up. A reduction of at least 25% in the primary outcome measure (responder criterion) was observed in 50% of the children in the NF group. In conclusion, behavioural improvements induced by NF training in children with ADHD were maintained at a 6-month follow-up. Though treatment effects appear to be limited, the results confirm the notion that NF is a clinically efficacious module in the treatment of children with ADHD.

Distinct EEG effects related to neurofeedback training in children with ADHD: a randomized controlled trial.

In a randomized controlled trial, neurofeedback (NF) training was found to be superior to a computerised attention skills training concerning the reduction of ADHD symptomatology (Gevensleben et al., 2009). The aims of this investigation were to assess the impact of different NF protocols (theta/beta training and training of slow cortical potentials, SCPs) on the resting EEG and the association between distinct EEG measures and behavioral improvements. In 72 (of initially 102) children with ADHD, aged 8-12, EEG changes after either a NF training (n=46) or the control training (n=26) could be studied. The combined NF training consisted of one block of theta/beta training and one block of SCP training, each block comprising 18 units of 50 minutes (balanced order). Spontaneous EEG was recorded in a two-minute resting condition before the start of the training, between the two training blocks and after the end of the training. Activity in the different EEG frequency bands was analyzed. In contrast to the control condition, the combined NF training was accompanied by a reduction of theta activity. Protocol-specific EEG changes (theta/beta training: decrease of posterior-midline theta activity; SCP training: increase of central-midline alpha activity) were associated with improvements in the German ADHD rating scale. Related EEG-based predictors were obtained. Thus, differential EEG patterns for theta/beta and SCP training provide further evidence that distinct neuronal mechanisms may contribute to similar behavioral improvements in children with ADHD.

Is neurofeedback an efficacious treatment for ADHD? A randomised controlled clinical trial.

BACKGROUND: For children with attention deficit/hyperactivity disorder (ADHD), a reduction of inattention, impulsivity and hyperactivity by neurofeedback (NF) has been reported in several studies. But so far, unspecific training effects have not been adequately controlled for and/or studies do not provide sufficient statistical power. To overcome these methodological shortcomings we evaluated the clinical efficacy of neurofeedback in children with ADHD in a multisite randomised controlled study using a computerised attention skills training as a control condition. METHODS: 102 children with ADHD, aged 8 to 12 years, participated in the study. Children performed either 36 sessions of NF training or a computerised attention skills training within two blocks of about four weeks each (randomised group assignment). The combined NF treatment consisted of one block of theta/beta training and one block of slow cortical potential (SCP) training. Pre-training, intermediate and post-training assessment encompassed several behaviour rating scales (e.g., the German ADHD rating scale, FBB-HKS) completed by parents and teachers. Evaluation ('placebo') scales were applied to control for parental expectations and satisfaction with the treatment. RESULTS: For parent and teacher ratings, improvements in the NF group were superior to those of the control group. For the parent-rated FBB-HKS total score (primary outcome measure), the effect size was .60. Comparable effects were obtained for the two NF protocols (theta/beta training, SCP training). Parental attitude towards the treatment did not differ between NF and control group. CONCLUSIONS: Superiority of the combined NF training indicates clinical efficacy of NF in children with ADHD. Future studies should further address the specificity of effects and how to optimise the benefit of NF as treatment module for ADHD.

Annotation: Tourette syndrome: a relentless drumbeat--driven by misguided brain oscillations.

OBJECTIVE: This annotation reviews recent evidence that points to the likely role of aberrant neural oscillations in the pathogenesis of Tourette syndrome (TS). METHODS: The available anatomic and electrophysiological findings in TS are reviewed in the context of an emerging picture of the crucial role that neural oscillations play in maintaining normal central nervous system (CNS) function. RESULTS: Neurons form behavior-dependent oscillating networks of various sizes and frequencies that bias input selection and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation as well as the transfer and long-term consolidation of information. Coherent network activity is likely to modulate sensorimotor gating as well as focused motor actions. When these networks are dysrhythmic, there may be a loss of control of sensory information and motor action. The known electrophysiological effects of medications and surgical interventions used to treat TS likely have an ameliorative effect on these aberrant oscillations. Similarly, a strong case can be made that successful behavioral treatments involve the willful training regions of the prefrontal cortex to engage in tic suppression and the performance of competing motor responses to unwanted sensory urges such that these prefrontal regions become effective modulators of aberrant thalamocortical rhythms. CONCLUSIONS: A deeper understanding of neural oscillations may illuminate the complex, challenging, enigmatic, internal world that is TS.

[Does a morning dose of Methylphenidate Retard reduce hyperkinetic symptoms in the afternoon?]. / Lassen sich hyperkinetische Auffälligkeiten am Nachmittag durch eine Morgengabe von Methylphenidat Retard vermindern?

OBJECTIVES: In order to treat children with Attention-deficit/Hyperactivity Disorder (ADHD) with a once-a-day stimulant several galenic approaches have been tried. The long acting methylphenidate (MPH, Medikinet-Retard) is a preparation with a two-step dynamic to release MPH (step one: acute; step two: prolonged). The efficacy of Medikinet-Retard, a new long-acting methylphenidate preparation, is analyzed based on the assessment of parents in the afternoon. METHODS: In a multicenter drug treatment study (placebo controlled, randomized, double-blind) 85 children (normal intelligence, age 6 to 16 years, diagnosis of ADHD according to DSM-IV) were investigated over 4 weeks with weekly visits. Forty-three children received Medikinet-Retard and forty-two children placebo. The weekly dose titration depending on body weight and symptomatology allowed a final maximum of 60 mg. The effects on ADHD as perveived by the parents were assessed weekly with a German symptom checklist for ADHD according to DSM-IV and ICD-10 (FBB-HKS). The differences between baseline and last week of treatment were compared statistically between groups. RESULTS: There was a large and statistically significant positive drug effect on ADHD symptomatology. The effect size of these differences was d = 1.2 (total score). Effects were found on inattention, hyperactivity and impulsity on the respective subscales. The efficacy of Medikinet-Retard was evaluated by the parents on an average as good. The rate of responders was four-times higher in the verum-group. The correlations of the changed scores in the parent ratings with the respective change scores in the teacher ratings were in the medium range. CONCLUSION: This is the first study with a German long-acting methylphenidate preparation (Medikinet-Retard). According to data based on parents' assessments, the drug showed very good clinical efficacy and safety in children with ADHD. Its two step galenic release of methylphenidate seems to be appropriate for a once-a-day (morning) stimulant in schoolchildren.

Training of slow cortical potentials in attention-deficit/hyperactivity disorder: evidence for positive behavioral and neurophysiological effects.

BACKGROUND: Learned self-control of slow cortical potentials (SCPs) may lead to behavioral improvement in attention-deficit/hyperactivity disorder (ADHD). Hence, training effects should also be reflected at the neurophysiological level. METHODS: Thirteen children with ADHD, aged 7-13 years, performed 25 SCP training sessions within 3 weeks. Before and after training, the German ADHD rating scale was completed by parents, and event-related potentials were recorded in a cued continuous performance test (CPT). For a waiting-list group of nine children with ADHD, the same testing was applied. RESULTS: ADHD symptomatology was reduced by approximately 25% after SCP training. Moreover, a decrease of impulsivity errors and an increase of the contingent negative variation were observed in the CPT task. CONCLUSIONS: This study provides first evidence for both positive behavioral and specific neurophysiological effects of SCP training in children with ADHD.

Developmental event-related gamma oscillations: effects of auditory attention.

This study describes maturational changes in topographical patterns, stability, and functional reactivity of auditory gamma band (31-63 Hz) responses (GBRs) as brain electrical correlates relevant for cognitive development during childhood. GBRs of 114 healthy children from 9 to 16 years were elicited in an auditory focused attention task requiring motor responding to targets, and analyzed by means of the wavelet transform (WT). The effects of age and task variables (attended side and stimulus type relevance) were examined for GBR power and phase-locking within 120 ms after stimulation. Similar to the spontaneous gamma band power, the power and phase-synchronization of GBRs did not depend on the age. However, the functional reactivity of GBRs at specific locations changed in the course of development. In 9-12-year-old children, GBRs at frontal locations were larger and better synchronized to target than to nontarget stimulus type, and were larger over the left hemisphere (contralateral to the responding hand), thus manifesting sensitivity to external stimulus features and motor task. In 13-16-year-old adolescents, GBRs at parietal sites were enhanced by active attending to the side of stimulation, thus being associated with a maintenance of attentional focus to stimulus location. The results indicate that (i) specific aspects of task-stimulus processing engage distinct spatially localized gamma networks at functionally relevant areas, and (ii) the neuronal substrates of gamma band networks and the ability to synchronize them in relation to task-specific processes are available in all age groups from 9 to 16 years. However, the mode and efficiency with which gamma networks can be entrained depends on the age. This age-dependent reactivity of GBRs to different task variables may reflect a transition in processing strategies emerging at approximately 12-13 years in relation to the maturation of cognitive and executive brain functions.