Search

Attention Deficit Hyperactivity Disorder (ADHD) negatively impacts Quality of Life (QoL) in adults. Earlier studies on pharmacological treatment have shown short-term beneficial effects on QoL. No data are available on long-term effects on multimodal psychosocial and/or pharmacological interventions. The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a prospective, multicenter randomized clinical trial, compared cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) and methylphenidate (MPH) with placebo (Plac) (2 × 2 factorial design over a period of 52 weeks). Change of QoL was measured after three months of intensive treatment, after 26 weeks, and after one year of maintenance treatment, using the Quality of life enjoyment and satisfaction questionnaire (Q-LES-Q, eight subscales). A follow-up was performed 1.5 years after treatment completion. Q-LES-Q scores were analyzed descriptively (means and confidence intervals). A linear regression model was used to test for significant differences between the four treatment arms. The full analysis set comprised 419 patients. Q-LES-Q scores increased between baseline and the end of treatment across all Q-LES-Q subscales (with exception of stable scores in the physical health/activities subscale in the CM + Plac group) and remained stable improved at follow-up. Regression analyses did not show any significant differences between the four treatment conditions. COMPAS is the first study to demonstrate stable and long-term improvements of QoL after multimodal treatment regardless of medication with MPH or Placebo, and regardless of structured GPT or individual CM. Trial registration: ISRCTN54096201.

Introduction: In depression treatment, most patients do not reach response or remission with current psychotherapeutic approaches. Major reasons for individual non-response are interindividual heterogeneity of etiological mechanisms and pathological forms, and a high rate of comorbid disorders. Personalised treatments targeting comorbidities as well as underlying transdiagnostic mechanisms and factors like early childhood maltreatment may lead to better outcomes. A Modular-Based Psychotherapy (MoBa) approach provides a treatment model of independent and flexible therapy elements within a systematic treatment algorithm to combine and integrate existing evidence-based approaches. By optimally tailoring module selection and application to the specific needs of each patient, MoBa has great potential to improve the currently unsatisfying results of psychotherapy as a bridge between disorder-specific and personalised approaches.Methods and analysis: In a randomized controlled feasibility trial (RCT), N=70 outpatients with episodic or persistent major depression, comorbidity and childhood maltreatment are treated in 20 individual sessions with MoBa or standard Cognitive Behavioural Therapy (CBT) for depression. The three modules of MoBa focus on deficits associated with early childhood maltreatment: the systems of negative valence, social processes, and arousal. According to a specific questionnaire-based treatment algorithm, elements from Cognitive Behavioral Analysis System of Psychotherapy (CBASP), Mentalization-Based Psychotherapy (MBT) and/or Mindfulness (MBCT) are integrated for a personalised modular procedure.As a proof of concept, this trial will provide evidence for the feasibility and efficacy (post-treatment and six month follow-up) of a modular add-on approach for patients with depression, comorbidities and a history of childhood maltreatment. Crucial feasibility aspects include targeted psychopathological mechanisms, selection (treatment algorithm), sequence and application of modules, as well as training and supervision of the study therapists. Ethics and dissemination: This study obtained approval from independent Ethics Committees. All findings will be disseminated broadly via peer-reviewed articles in scientific journals and contributions to national and international conferences.Trial registration: German Clinical Trials Register (www.drks.de): DRKS00022093.

IntroductionIn depression treatment, most patients do not reach response or remission with current psychotherapeutic approaches. Major reasons for individual non-response are interindividual heterogeneity of etiological mechanisms and pathological forms, and a high rate of comorbid disorders. Personalised treatments targeting comorbidities as well as underlying transdiagnostic mechanisms and factors like early childhood maltreatment may lead to better outcomes. A modular-based psychotherapy (MoBa) approach provides a treatment model of independent and flexible therapy elements within a systematic treatment algorithm to combine and integrate existing evidence-based approaches. By optimally tailoring module selection and application to the specific needs of each patient, MoBa has great potential to improve the currently unsatisfying results of psychotherapy as a bridge between disorder-specific and personalised approaches.Methods and analysisIn a randomised controlled feasibility trial, N=70 outpatients with episodic or persistent major depression, comorbidity and childhood maltreatment are treated in 20 individual sessions with MoBa or standard cognitive–behavioural therapy for depression. The three modules of MoBa focus on deficits associated with early childhood maltreatment: the systems of negative valence, social processes and arousal. According to a specific questionnaire-based treatment algorithm, elements from cognitive behavioural analysis system of psychotherapy, mentalisation-based psychotherapy and/or mindfulness-based cognitive therapy are integrated for a personalised modular procedure.As a proof of concept, this trial will provide evidence for the feasibility and efficacy (post-treatment and 6-month follow-up) of a modular add-on approach for patients with depression, comorbidities and a history of childhood maltreatment. Crucial feasibility aspects include targeted psychopathological mechanisms, selection (treatment algorithm), sequence and application of modules, as well as training and supervision of the study therapists.Ethics and disseminationThis study obtained approval from the independent Ethics Committees of the University of Freiburg and the University of Heidelberg. All findings will be disseminated broadly via peer-reviewed articles in scientific journals and contributions to national and international conferences.Trial registration numberDRKS00022093.

Zusammenfassung. In der Behandlung der adulten ADHS haben sich sowohl pharmakologische Interventionen als auch psychosoziale Behandlungen als wirksam erwiesen. In der täglichen klinischen Routine wird die Behandlung jedoch weniger von den Ergebnissen klinischer Studien als von Behandlungsrichtlinien und Anforderungen nationaler Institutionen (Gemeinsamer Bundesausschuss) beeinflusst. Der Hauptaspekt dieser Vorschriften ist die Anforderung, dass ein stufenweiser Behandlungsansatz, beginnend mit niederschwelligen Interventionen, am sinnvollsten für die Behandlung bei adulten ADHS-Patienten ist. Leider gibt es bis heute fast ausschließlich klinische Studien, welche die Auswirkungen einzelner Therapiestrategien erforschen. Das gestufte Versorgungsmodell scheint noch nicht ausreichend validiert. Genau hier möchte die im Folgenden beschriebene ESCAlate-Studie ansetzen. Bei ESCAlate handelt es sich um eine randomisierte, kontrollierte Studie. Es sollen 279 Patienten im Alter zwischen 16.00 und 45.11 Jahren in das Behandlungsprogramm, welches sich in mehrere Abschnitte gliedert, aufgenommen werden. In einem ersten Behandlungsabschnitt werden die Patienten nach dem Zufallsverfahren in drei Gruppen eingeteilt: Psychoedukation im Einzelsetting (PE), Telefonassistierte Selbsthilfe (TASH) oder Wartekontrollgruppe. Alle Patienten der Wartegruppe erhalten nach dreimonatiger Wartezeit eine Behandlung mit TASH. Im zweiten Behandlungsabschnitt werden die Patienten entsprechend der Schwere ihrer persistierenden Symptome in die drei Gruppen Full-Responder, Partial-Responder und Non-Responder eingeteilt. Patienten, welche als Full-Responder eingestuft wurden erhalten ein verhaltenstherapeutisch orientiertes Coaching. Partial-Responder erhalten ebenfalls dieses Coaching, wobei in dieser Gruppe der Zufall entscheidet, ob die Patienten zusätzlich ein Neurofeedbacktraining (NF) erhalten. Non-Responder erhalten eine pharmakologische Behandlung mit Methylphenidat. Hier entscheidet ebenfalls der Zufall, ob die Patienten zusätzlich ein Neurofeedbacktraining erhalten. ESCAlate zeichnet sich durch eine relativ naturalistische Stichprobenzusammensetzung aus, da auf hochspezifische Ein- und Ausschlusskriterien verzichtet wurde, um eine Patientenstichprobe zu erhalten, die die Patienten der alltäglichen klinischen Routine in den Praxen widerspiegelt. Die Wirksamkeit einer evidenzbasierten Intervention mit gestufter Behandlung wird durch primäre (Verringerung des Schweregrads der ADHS-Symptome) und sekundäre Ergebnisse (funktionelle Ergebnisse; z.B. Lebensqualität, Ärger-Management, Steigerung des psychosozialen Wohlbefindens) untersucht. Prädiktoren für therapeutisches Ansprechen bzw. Nicht-Ansprechen werden bei jedem Schritt der Intervention evaluiert. Darüber hinaus können eventuelle geschlechtsspezifische Unterschiede untersucht werden.

Background Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a - yet experimental - treatment for major depressive disorder (MDD) and other treatment refractory psychiatric diseases. First experiences have been reported from two open label pilot trials in major depression (MDD) and long-term effectiveness for MDD (50 months) has been reported. Objective To give a detailed description of the surgical technique for DBS of the superolateral branch of the medial forebrain bundle (slMFB) in MDD. Methods Surgical experience from bilateral implantation procedures in n = 24 patients with MDD is reported. The detailed procedure of tractography-assisted targeting together with detailed electrophysiology in 144 trajectories in the target region (recording and stimulation) is described. Achieved electrode positions were evaluated based on postoperative helical CT and fused to preoperative high resolution anatomical magnetic resonance imaging (MRI; Philips Medical Systems, Best, Netherlands), including the pre-operative diffusion tensor imaging (DTI) tractographic information (StealthViz DTI, Medtronic, USA; Framelink 5.0, Medtronic, USA). Midcommissural point (MCP) coordinates of effective contact (EC) location, together with angles of entry into the target region were evaluated. To investigate incidental stimulation of surrounding nuclei (subthalamic nucleus, STN; substantia nigra, SNr; and red nucleus, RN) as a possible mechanism, a therapeutic triangle (TT) was defined, located between these structures (based on MRI criteria in T2) and evaluated with respect to EC locations. Results Bilateral slMFB DBS was performed in all patients. We identified an electrophysiological environment (defined by autonomic reaction, passive microelectrode recording, acute effects and oculomotor effects) that helps to identify the proper target site on the operation table. Postoperative MCP-evaluation of effective contacts (EC) shows a significant variability with respect to localization. Evaluation of the TT shows that responders will typically have their active contacts inside the triangle and that surrounding nuclei (STN, SNr, RN) are not directly hit by EC, indicating a predominant white matter stimulation. The individual EC position within the triangle cannot be predicted and is based on individual slMFB (tractography) geometry. There was one intracranial bleeding (FORESEE I study) during a first implantation attempt in a patient who later received full bilateral implantation. Typical oculomotor side effects are idiosyncratic for the target region and at inferior contacts. Conclusion The detailed surgical procedure of slMFB DBS implantation has not been described before. The slMFB emerges as an interesting region for the treatment of major depression (and other psychiatric diseases) with DBS. So far it has only been successfully researched in open label clinical case series and in 15 patients published. Stimulation probably achieves its effect through direct white-matter modulation of slMFB fibers. The surgical implantation comprises a standardized protocol combining tractographic imaging based on DTI, targeting and electrophysiological evaluation of the target region. To this end, slMFB DBS surgery is in technical aspects comparable to typical movement disorder surgery. In our view, slMFB DBS should only be performed under tractographic assistance., Graphical abstract Unlabelled Image, Highlights • The slMFB is an emerging target for DBS in therapy refractory Depression. • The therapeutic effect is related to modulation of white matter. • Surgery for slMFB DBS is tractography assisted surgery. • DBS of the slMFB is in many aspects similar to movement disorder surgery.

Simple Summary Prostate cancer (PCa) is the most diagnosed malignancy of men worldwide, and radiotherapy (RT) is a main treatment option for patients in all disease stages. Modern diagnostic imaging and RT techniques enable an effective and safe delivery of high RT doses and a reduction of treatment time. We present a study protocol of a phase III trial implementing most modern imaging techniques and RT approaches. We compare the standard RT treatment with an RT concept of reduced treatment time and focal dose escalation based on the patient’s individual tumor morphology. This HypoFocal-SBRT trial aims to individualize treatment of PCa patients. Abstract Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose–response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.

Zusammenfassung Nicht zuletzt veranlasst durch Publikationen aus den skandinavischen Endoprothesen- und Kreuzbandregistern hat die Registerforschung in den vergangenen Jahren zunehmend an Stellenwert gewonnen. Haufig beeindrucken Publikationen aus diesen Registern durch grose Fallzahlen und teilweise spektakulare Aussagen. Aus biostatistischer Sicht weisen jedoch gerade Registerdaten eine grose Anfalligkeit fur methodische Schwierigkeiten auf, die eine wichtige Limitation darstellen. So muss grundsatzlich die Validitat der Daten, sogenannte „Confounder" und die Identifikation potentieller Verzerrungseffekte sowie der Umgang mit diesen Faktoren im Rahmen der Dateninterpretation berucksichtigt werden, um Register als moderne Instrumente der Versorgungsforschung effektiv und angemessen nutzen zu konnen. Der vorliegende Artikel soll eine kurze Ubersicht uber die Chancen und Risiken bei der Erhebung, Auswertung und Interpretation von Registerdaten geben.

BACKGROUND AND PURPOSE: New deep brain stimulation leads with electrode contacts that are split along their circumference allow steering of the electrical field in a predefined direction. However, imaging-assisted directional stimulation requires detailed knowledge of the exact orientation of the electrode array. The purpose of this study was to evaluate whether this information can be obtained by rotational 3D fluoroscopy. MATERIALS AND METHODS: Two directional leads were inserted into a 3D-printed plaster skull filled with gelatin. The torsion of the lead tip versus the lead at the burr-hole level was investigated. Then, 3 blinded raters evaluated 12 3D fluoroscopies with random lead orientations. They determined the lead orientation considering the x-ray marker only and considering the overlap of the gaps between the contact segments. Intraclass correlation coefficients and an extended version of the Bland-Altman plot were used to determine interrater reliability and agreement of the measurements of the different raters. RESULTS: Electrode torsion of up to 35° could be demonstrated. Evaluation of the lead rotation considering the x-ray marker only revealed limits of agreement of ±9.37° and an intraclass correlation coefficient of 0.9975. In addition, taking into account the lines resulting from overlapping of the gaps between the electrode segments, the limits of agreement to the mean were ±2.44° and an intraclass correlation coefficient of 0.9998. CONCLUSIONS: In directional deep brain stimulation systems, rotational 3D fluoroscopy combined with the described evaluation method allows for determining the exact orientation of the leads, enabling the full potential of imaging-assisted personalized programming.

Risk and prognostic factors in epidemiological and clinical research are often semicontinuous such that a proportion of individuals have exposure zero, and a continuous distribution among those exposed. We call this a spike at zero (SAZ). Typical examples are consumption of alcohol and tobacco, or hormone receptor levels. To additionally model non-linear functional relationships for SAZ variables, an extension of the fractional polynomial (FP) approach was proposed. To indicate whether or not a value is zero, a binary variable is added to the model. In a two-stage procedure, called FP-spike, it is assessed whether the binary variable and/or the continuous FP function for the positive part is required for a suitable fit. In this paper, we compared the performance of two approaches – standard FP and FP-spike – in the Cox model in a motivating example on breast cancer prognosis and a simulation study. The comparisons lead to the suggestion to generally using FP-spike rather than standard FP when the SAZ effect is considerably large because the method performed better in real data applications and simulation in terms of deviance and functional form. Abbreviations: CI: confidence interval; FP: fractional polynomial; FP1: first degree fractional polynomial; FP2: second degree fractional polynomial; FSP: function selection procedure; HT: hormone therapy; OR: odds ratio; SAZ: spike at zero

Background Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. Objective This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. Methods This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson’s Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson’s disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. Results At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. Conclusions The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the “quality of life” outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients’ quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. Trial Registration ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).

Background Over the last decade, a wide range of attention-deficit/hyperactivity disorder (ADHD) treatment approaches for adults, including both pharmacological interventions and psychosocial treatments, have been proposed and observed to be efficient. In practice, individual treatment concepts are based on results of clinical studies as well as international guidelines (NICE Guidelines) that recommend a step-by-step treatment approach. Since the evidence supporting this approach is limited, the aim of the present study is to determine an optimal intervention regarding severity levels of ADHD symptomatology conducting a randomized controlled trial. Method We aim to include 279 ADHD subjects aged between 16 and 45 years. First, participants are randomized to either a face-to-face psychoeducation, telephone assisted self-help (TASH), or a waiting control group (Step 1). All participants assigned to the control group are treated using TASH after a 3-month waiting period. Participants are then allocated to one of three groups, based on their remaining severity level of ADHD symptoms, as (1) full responder, (2) partial responder, or (3) non-responder (Step 2). Full responders receive counseling, partial responders receive either counseling only or counseling and neurofeedback (NF), and non-responders receive either pharmacological treatment only or pharmacological treatment and NF, followed by a 3 month period without intervention. Discussion The naturalistic sample is one of the study’s advantages, avoiding highly selective inclusion or exclusion criteria. The efficacy of an evidence-based stepped care intervention is explored by primary (reduction of severity of ADHD symptoms) and secondary outcomes (functional outcomes, e.g., quality of life, anger management, enhancement of psychosocial well-being). Predictors of therapeutic response and non-response are being investigated at each step of intervention. Further, sex differences are also being explored. Trial registration This study is registered by the German Trial Register (reference number: DRKS00008975), 23 October 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-2665-9) contains supplementary material, which is available to authorized users.

For safe deep brain stimulation (DBS) planning, an accurate visualization and localization of vessels is mandatory. Contrast enhanced (ce) MRI depicts both arteries and veins. Computed tomography angiography (CTA) detects arteries with high geometric accuracy. We routinely combine both modalities for DBS planning. A total of 222 trajectories in a consecutive series of 113 patients who underwent DBS operations were included. In all trajectories, the number of veins and arteries in a 10-mm diameter around the planned trajectory were counted in a ceMRI and a CTA. If a vessel was visible in both modalities, the distance was measured. A total of 370 vessels were counted. Two hundred forty vessels (65%) were visible in both modalities. With 134 of the vessels, we detected a difference of the vessel’s location with an average distance of 1.24 mm (SD 0.58). Eighty vessels (22%) were visible only in the ceMRI, 50 vessels (13%) only in the CTA. We had four bleedings (1.8% per lead) of which one was symptomatic (0.45%). The majority of vessels were visible in both modalities; however, in more than half of these cases, the location was not identical. Here, the location in the CTA can be regarded as the ground truth. Moreover, both the CTA and the ceMRI depicted vessels not seen in the other imaging modality. We therefore assume that the combination of both imaging modalities for DBS planning increases the chance to detect vascular conflicts along the trajectory, thus reducing the risk of intracranial bleeding.

In epidemiology and clinical research, there is often a proportion of unexposed individuals resulting in zero values of exposure, meaning that some individuals are not exposed and those exposed have some continuous distribution. Examples are smoking or alcohol consumption. We will call these variables with a spike at zero (SAZ). In this paper, we performed a systematic investigation on how to model covariates with a SAZ and derived theoretical odds ratio functions for selected bivariate distributions. We consider the bivariate normal and bivariate log normal distribution with a SAZ. Both confounding and effect modification can be elegantly described by formalizing the covariance matrix given the binary outcome variable Y. To model the effect of these variables, we use a procedure based on fractional polynomials first introduced by Royston and Altman (1994, Applied Statistics 43: 429–467) and modified for the SAZ situation (Royston and Sauerbrei, 2008, Multivariable model-building: a pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables, Wiley; Becher et al., 2012, Biometrical Journal 54: 686–700). We aim to contribute to theory, practical procedures and application in epidemiology and clinical research to derive multivariable models for variables with a SAZ. As an example, we use data from a case–control study on lung cancer.

Background The ESCAschool study addresses the treatment of school-age children with attention-deficit/hyperactivity disorder (ADHD) in a large multicentre trial. It aims to investigate three interrelated topics: (i) Clinical guidelines often recommend a stepped care approach, including different treatment strategies for children with mild to moderate and severe ADHD symptoms, respectively. However, this approach has not yet been empirically validated. (ii) Behavioural interventions and neurofeedback have been shown to be effective, but the superiority of combined treatment approaches such as medication plus behaviour therapy or medication plus neurofeedback compared to medication alone remains questionable. (iii) Growing evidence indicates that telephone-assisted self-help interventions are effective in the treatment of ADHD. However, larger randomised controlled trials (RCTs) are lacking. This report presents the ESCAschool trial protocol. In an adaptive treatment design, two RCTs and additional observational treatment arms are considered. Methods The target sample size of ESCAschool is 521 children with ADHD. Based on their baseline ADHD symptom severity, the children will be assigned to one of two groups (mild to moderate symptom group and severe symptom group). The adaptive design includes two treatment phases (Step 1 and Step 2). According to clinical guidelines, different treatment protocols will be followed for the two severity groups. In the moderate group, the efficacy of telephone-assisted self-help for parents and teachers will be tested against waitlist control in Step 1 (RCT I). The severe group will receive pharmacotherapy combined with psychoeducation in Step 1. For both groups, treatment response will be determined after Step 1 treatment (no, partial or full response). In severe group children demonstrating partial response to medication, in Step 2, the efficacy of (1) counselling, (2) behaviour therapy and (3) neurofeedback will be tested (RCT II). All other treatment arms in Step 2 (severe group: no or full response; moderate group: no, partial or full response) are observational. Discussion The ESCAschool trial will provide evidence-based answers to several important questions for clinical practice following a stepped care approach. The adaptive study design will also provide new insights into the effects of additional treatments in children with partial response. Trial registration German Clinical Trials Register (DRKS) DRKS00008973 . Registered 18 December 2015.

BACKGROUND Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. OBJECTIVE This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. METHODS This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson’s Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson’s disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. RESULTS At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. CONCLUSIONS The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the “quality of life” outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients’ quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. CLINICALTRIAL ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).

Background Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim-DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used. Objective This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient. Methods The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg. Results Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment. Conclusions The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery. ClinicalTrial ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS).

BACKGROUND AND PURPOSE: Diffusion tensor imaging fiber tractography–assisted planning of deep brain stimulation is an emerging technology. We investigated its accuracy by using electrophysiology under clinical conditions. We hypothesized that a level of concordance between electrophysiology and DTI fiber tractography can be reached, comparable with published modeling approaches for deep brain stimulation surgery. MATERIALS AND METHODS: Eleven patients underwent subthalamic nucleus deep brain stimulation. DTI scans and high-resolution T1- and T2-weighted MR imaging was performed at 3T. Corticospinal tracts were traced. We studied electrode positions and current amplitudes that elicited corticospinal tract effects during the operation to determine relative corticospinal tract distance. Postoperatively, 3D deep brain stimulation electrode contact locations and stimulation patterns were applied for the same corticospinal tract distance estimation. RESULTS: Intraoperative electrophysiologic ( n = 40) clinical effects in 11 patients were detected. The mean intraoperative electrophysiologic corticospinal tract distance was 3.0 ± 0.6 mm; the mean image-derived corticospinal tract distance (DTI fiber tractography) was 3.0 ± 1.3 mm. The 95% limits of agreement were ±2.4 mm. Postoperative electrophysiology ( n = 44) corticospinal tract activation effects were encountered in 9 patients; 39 were further evaluated. Mean electrophysiologic corticospinal tract distance was 3.7 ± 0.7 mm; for DTI fiber tractography, it was 3.2 ± 1.9 mm. The 95% limits of agreement were ±2.5 mm. CONCLUSIONS: DTI fiber tractography depicted the medial corticospinal tract border with proved concordance. Although the overall range of measurements was relatively small and variance was high, we believe that further use of DTI fiber tractography to assist deep brain stimulation procedures is advisable if inherent limitations are respected. These results confirm our previously published electric field simulation studies.

In most epidemiologic studies and in clinical research generally, there are variables with a spike at zero, namely variables for which a proportion of individuals have zero exposure (e.g., never smokers) and among those exposed the variable has a continuous distribution. Different options exist for modeling such variables, such as categorization where the nonexposed form the reference group, or ignoring the spike by including the variable in the regression model with or without some transformation or modeling procedures. It has been shown that such situations can be analyzed by adding a binary indicator (exposed/nonexposed) to the regression model, and a method based on fractional polynomials with which to estimate a suitable functional form for the positive portion of the spike-at-zero variable distribution has been developed. In this paper, we compare different approaches using data from 3 case-control studies carried out in Germany: the Mammary Carcinoma Risk Factor Investigation (MARIE), a breast cancer study conducted in 2002-2005 (Flesch-Janys et al., Int J Cancer. 2008;123(4):933-941); the Rhein-Neckar Larynx Study, a study of laryngeal cancer conducted in 1998-2000 (Dietz et al., Int J Cancer. 2004;108(6):907-911); and a lung cancer study conducted in 1988-1993 (Jockel et al., Int J Epidemiol. 1998;27(4):549-560). Strengths and limitations of different procedures are demonstrated, and some recommendations for practical use are given.

In epidemiology and clinical research, predictors often take value zero for a large amount of observations while the distribution of the remaining observations is continuous. These predictors are called variables with a spike at zero. Examples include smoking or alcohol consumption. Recently, an extension of the fractional polynomial (FP) procedure, a technique for modeling nonlinear relationships, was proposed to deal with such situations. To indicate whether or not a value is zero, a binary variable is added to the model. In a two stage procedure, called FP-spike, the necessity of the binary variable and/or the continuous FP function for the positive part are assessed for a suitable fit. In univariate analyses, the FP-spike procedure usually leads to functional relationships that are easy to interpret. This paper introduces four approaches for dealing with two variables with a spike at zero (SAZ). The methods depend on the bivariate distribution of zero and nonzero values. Bi-Sep is the simplest of the four bivariate approaches. It uses the univariate FP-spike procedure separately for the two SAZ variables. In Bi-D3, Bi-D1, and Bi-Sub, proportions of zeros in both variables are considered simultaneously in the binary indicators. Therefore, these strategies can account for correlated variables. The methods can be used for arbitrary distributions of the covariates. For illustration and comparison of results, data from a case-control study on laryngeal cancer, with smoking and alcohol intake as two SAZ variables, is considered. In addition, a possible extension to three or more SAZ variables is outlined. A combination of log-linear models for the analysis of the correlation in combination with the bivariate approaches is proposed.