Feasibility of a Complex Setting for Assessing Sleep and Circadian Rhythmicity in a Fragile X Cohort.

INTRODUCTION: Sleep, circadian rhythms, (mental) health, and development are assumed to be intertwined. However, differentiated and reliable parameters of sleep and circadian rhythms are particularly difficult to assess for Fragile X (FXS) individuals. As those parameters need to be observed in complex settings, the feasibility of measurements for people with FXS was to be proven. Findings from this pilot study can inform further research and help to estimate sample sizes for future studies on FXS patients. METHODS AND SAMPLE: Nine individuals (male and female) with full mutation of the FMR1 gene were integrated in the study and underwent a complex measurement including actigraphy, sleep log, and 24-h saliva sampling in order to examine profiles of melatonin and cortisol, and a polysomnography. RESULTS: Seven actigraphy profiles, eight sleep logs, eight saliva profiles and seven polysomnographic data sets were collected. Complete data were analyzed for six individuals [mean age 14.87 years (SD 4.12), mean BMI 25.90 (SD 4.44)] were collected. No drop outs due to the constraints of the assessment were registered. DISCUSSION: All assessments and the setting in total were tolerated well by participants and caregivers. Procedures were adapted to individual needs of the participants. CONCLUSION: All its components and the setting in total are absolutely feasible in the specific population of FXS individuals. Losses during consenting and recruiting have to be planned as well as high amounts of interindividual variances have to be taken into account.

[The Care of Intellectually Disabled Children and Adolescents with Psychiatric Disorders in Hospitals for Child and Adolescent Psychiatry and Psychotherapy in Germany]. / Kinder- und jugendpsychiatrische Versorgung von Kindern und Jugendlichen mit Intelligenzminderung und psychischen Störungen in Deutschland.

OBJECTIVE: This study explores the care situation of children and adolescents with intellectual disabilities (ID) suffering from mental problems in Germany in 2014. It complements the study of Hennicke, which was conducted a decade ago. METHOD: All clinics and departments of child and adolescent psychiatry in Germany (n=138) were contacted via mail or personally and requested to fill out a questionnaire. We received data from one-third (n=46) of all hospitals contacted. RESULTS: Eight hospitals (17%) offered specialized services for this client base as either inpatient or outpatient treatment. Three hospitals (7%) provided both. Average proportions of children with ID treated were 6.6% for inpatient, 7.9% for day hospital, and 3% for outpatient services. More than half of responding institutions (54%) judged inpatient services as being defective. Slightly less (43%) reported their outpatient services as being defective or inadequate. For the treatment of mental disorders in young patients with ID, different treatments were used, according to the degree of the ID and applying the standard of child and adolescent psychiatry. Some interventions were used independently of the degree of ID, such as practical exercises, interventions in the patient environment (parents, family). Other interventions, such as psychotherapy were used to a lesser degree when the degree of ID increased. Youth with mild ID received twice as much psychotherapeutic interventions compared to children and adolescents with severe ID. The latter received more psychopharmacotherapy instead. Youth with severe ID received twice as much (67%) psychotropic medication compared to children and adolescents with mild ID. CONCLUSION: The defective care situation of the highly vulnerable children and adolescents with ID did not change much between 2004 and 2014. The amount of specialized care services increased only marginally. Non-pharmacological treatments were used to a larger extent, compared to psychotropic medication, independent of the degree of ID.

The role of sleep problems and circadian clock genes in attention-deficit hyperactivity disorder and mood disorders during childhood and adolescence: an update.

A more recent branch of research describes the importance of sleep problems in the development and treatment of mental disorders in children and adolescents, such as attention-deficit hyperactivity disorder (ADHD) and mood disorders (MD). Research about clock genes has continued since 2012 with a focus on metabolic processes within all parts of the mammalian body, but particularly within different cerebral regions. Research has focused on complex regulatory circuits involving clock genes themselves and their influence on circadian rhythms of diverse body functions. Current publications on basic research in human and animal models indicate directions for the treatment of mental disorders targeting circadian rhythms and mechanisms. The most significant lines of research are described in this paper.

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study.

BACKGROUND: As data on the phenotype, characteristics and management of patients with Fragile X Syndrome (FXS) are limited, we aimed to collect such data in Germany in experienced centres involved in the treatment of such patients. METHODS: EXPLAIN-FXS is a prospective observational (non-interventional) study (registry) performed between April 2013 and January 2016 at 18 sites in Germany. Requirements for patient participation included confirmed diagnosis of FXS by genetic testing (>200 CGG repeats) and written informed consent. Patients were followed for up to 2 years. RESULTS: Seventy-five patients (84.0 % males, mean age 16.7 ± 14.5 years, ranging from 2 - 82 years) were analysed. The mean 6-item score, determined according to Giangreco (J Pediatr 129:611-614, 1996), was 6.9 ± 2.5 points. At least one neurological finding each was noted in 53 patients (69.7 %). Specifically, ataxia was noted in 5 patients (6.6 %), lack of fine motor skills in 40 patients, (52.6 %), muscle tonus disorder in 4 patients (5.3 %), and other neurological disorders in 39 patients (51.3 %). Spasticity was not noted in any patient. Seizures were reported in 6 patients (8.1 %), anxiety disorders in 22 patients (30.1 %), depression in 7 patients (9.6 %), ADHD/ADD in 36 patients (49.3 %), impairment of social behavior in 39 patients (53.4 %), and other comorbidities in 23 patients (31.5 %). The mean Aberrant Behaviour Checklist Community Edition (ABC-C) score on behavioral symptoms, obtained in 71 patients at first documentation, was 48.4 ± 27.8 (median 45.0, range 5-115). The mean visual analogue scale (VAS) score, obtained in 59 patients at first documentation, was 84.9 ± 14.6 points (median 90; range 50 - 100). CONCLUSIONS: This report describes the largest cohort of patients with FXS in Europe. The reported observations indicate a substantial burden of disease for patients and their caregivers. Based on these observations, an early expert psychiatric diagnosis is recommended for suspected FXS patients. Further recommendations include multimodal and multi-professional management that is tailored to the individual patient's needs. TRIAL REGISTRATION: The ClinTrials.gov identifier is NCT01711606 . Registered on 18 October 2012.

Objective measurement of tissue tension in myofascial trigger point areas before and during the administration of anesthesia with complete blocking of neuromuscular transmission.

OBJECTIVES: Myofascial trigger points (MTPs) are extremely frequent in the human musculoskeletal system. Despite this, little is known about their etiology. Increased muscular tension in the trigger point area could be a major factor for the development of MTPs. To investigate the impact of muscular tension in the taut band with an MTP and thereby, the spinal excitability of associated segmental neurons, we objectively measured the tissue tension in MTPs before and during the administration of anesthesia using a transducer. METHODS: Three target muscles (m. temporalis, upper part of m. trapezius, and m. extensor carpi radialis longus) with an MTP and 1 control muscle without an MTP were examined in 62 patients scheduled for an operation. RESULTS: We found significant 2-way interactions (ANOVA, P<0.05) between the analyzed regions of the target muscles dependent on the time of measurement, that is, before and during a complete blocking of neuromuscular transmission. These effects could be demonstrated for each target muscle separately. DISCUSSION: An increased muscle tension in MTPs, and not a primary local inflammation with enhanced viscoelasticity, was the main result of our investigation. We interpret this increased muscular tension in the taut band with an MTP as increased spinal segmental excitability. In line with this, we assume a predominant, but not unique, impact of increased spinal excitability resulting in an augmented tension of segmental-associated muscle fibers for the etiology of MTP. Consequently, postisometric relaxation might be a promising therapeutic option for MTPs.

EXPLAIN Fragile-X: an explorative, longitudinal study on the characterization, treatment pathways, and patient-related outcomes of Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS), caused by a mutation of the FMR1 gene on the X chromosome, is the most common inherited form of intellectual disability and autism spectrum disorders. Comprehensive data are lacking, however, on the characteristics and management patients with FXS in Germany. METHODS/DESIGN: EXPLAIN is a prospective, observational, longitudinal registry with a non-probability sampling approach. It collects data on patient characteristics, therapeutic interventions, psychosocial parameters (including those of family members and caregivers), quality of life of caregiver and patient, caregiver burden, and health economic parameters, such as hospitalisation time. It is designed to include data from 300 patients in ambulatory care from about 50 centres that employ psychiatrists, paediatricians, neurologists, and other relevant specialists, in Germany. The study was initiated in March, 2013. Patients will be followed for at least two years. DISCUSSION: The registry is expected to provide much-needed data on the characteristics and management of patients with FXS in Germany. It will also allow comparisons with other countries, and will enable gap analyses based on current guidelines for management of these patients. TRIAL REGISTRATION: The ClinicalTrials.gov identifier is NCT01711606.

Who wants to become a child psychiatrist? Lessons for future recruitment strategies from a student survey at seven German medical schools.

OBJECTIVE: The objective of this survey was to investigate undergraduate German medical students' attitudes toward child and adolescent psychiatry (CAP) and to describe the characteristics of students considering CAP as a possible career choice. METHODS: The authors conducted a cross-sectional, multicenter survey of medical students (at the time of their first CAP lecture) at seven German medical schools. The students completed an anonymous self-report questionnaire, asking about their attitude toward CAP and their view of CAP as a possible career choice. RESULTS: Of the 574 students, 42.9% had "high" or "very high" interest in CAP, and 59.4% rated CAP basic knowledge as "highly" or "very highly" relevant for their prospective work as physicians. CAP was a possible career choice for 25.4%. The most frequently mentioned reasons for choosing CAP were interesting clinical cases (65.8%), helping ill children (52.1%), and close patient-physician contact (50.7%). The most frequently mentioned reasons against this decision were a definite decision for another subspecialty (54.8%), expected difficulties in working with parents and family members (35.3%), and an expected high emotional burden (29.6%). In addition to the highly significant correlation with general interest in CAP, students with previous experience in general psychiatry and CAP clinical courses, as well as female students and students with relatives or acquaintances with CAP-related disorders, showed the highest interest in CAP as a possible career choice. CONCLUSION: The majority of the students surveyed showed a positive attitude toward CAP and considered CAP basic knowledge to be relevant for their future work. When designing recruitment strategies, it may be helpful to consider that CAP exposure early in the curriculum might be decisive and that students with previous clinical courses in this field, as well as female students, showed the highest interest in CAP as a possible career choice.

The role of sleep problems and circadian clock genes in childhood psychiatric disorders.

CLOCK gene research and the analysis of circadian rhythmicity on the behavioural, cellular and molecular level are increasingly contributing to accumulate clinically relevant knowledge in the fields of neuroscience, psychopharmacology and adult psychiatry. However, the role of circadian phenomena, including sleep alterations in mental disorders during childhood and adolescence remains largely enigmatic. Fortunately, recent publications have addressed this problem and there is now some evidence available highlighting the relevance of CLOCK genes in conditions, such as ADHD, mood disorders, schizophrenia and anxiety disorders.

Intelligence moderates impulsivity and attention in ADHD children: an ERP study using a go/nogo paradigm.

OBJECTIVES: If the cardinal symptoms of ADHD - hyperactivity, impulsivity and inattention - are combined with a learning disability (70 ≥ IQ < 85), the question arises whether a child shows hyperkinetic behaviour because of intellectual overload in a challenging situation, for example at school. Perhaps, this behaviour is not a primary attention deficit disorder but an impulse control disorder, determined by the primarily intelligence level. It raised the question whether attention deficit and impulse control regarded as behavioural inhibition deficit may depend on intelligence and therefore should be separated into distinct clinical entities. METHODS: A total of 45 children (15 with ADHD, 15 with learning disabilities (LD), 15 with ADHD and learning disabilities) were compared in a matched-pair design with 42 control children using a go/no go paradigm (visual continuous performance test, CPT). The dependent variable was the target P3 amplitude, averaged from a 10-20 EEG measurements under distinct trigger conditions. For statistical analysis, a three-factor analysis of variance (MANOVA) with repeated measurements was used. In a subsequent regression analysis with residuals, the influence of intelligence (IQ) was calculated and a "parallel analysis of variance" was conducted. RESULTS: No differences in the P3 amplitudes in the comparison ADHD-control group were found. Reduced P3 amplitudes as main effects in the LD group compared with controls were found and a significant group-dependent interaction on reduced P3 amplitudes comparing ADHD + LD versus control group. Using residuals (IQ), this interaction was not longer verifiable. CONCLUSION: Impulsivity and attention deficit as the cardinal symptoms of ADHD, regarded as behavioural inhibition deficit, are essentially moderated by the primary intelligence, rather than by an attention deficit. The lower the IQ, the more ADHD surfaces as a disturbed impulsivity and lesser as an attention deficit.

A double-blind, randomized, placebo/active controlled crossover evaluation of the efficacy and safety of Ritalin ® LA in children with attention-deficit/hyperactivity disorder in a laboratory classroom setting.

OBJECTIVES: The primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. METHODS: A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. RESULTS: In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. CONCLUSION: Ritalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

A randomized, rater-blinded, crossover study comparing the clinical efficacy of Ritalin(®) LA (methylphenidate) treatment in children with attention-deficit hyperactivity disorder under different breakfast conditions over 2 weeks.

Several extended-release methylphenidate medications are available for treatment of children with ADHD. Pharmacokinetic investigations suggest that the serum levels of methylphenidate are partially altered when the medication is taken without breakfast. Clinical data comparing different breakfast situations are missing. In this study, different breakfast compositions and their influence on treatment with Ritalin LA are investigated. A total of 150 patients were enrolled in a rater-blinded, randomized crossover trial that compared a minimal breakfast with a standard breakfast in patients under stable treatment with Ritalin LA. Ratings for clinical efficacy were carried out after 1 week by teachers and parents (FBB-ADHS), as well as physicians (CGI). Additionally, a math test was administered to the patients. Of the total patients, 144 finished the trial with a breakfast compliance of 93%. All of the clinical rating scales showed consistently no difference between the two breakfast conditions. Non-inferiority of minimal breakfast versus standard breakfast was shown to be statistically significant (FBB-AHDS(Teacher): 0.97 with minimal breakfast, 1.01 with standard breakfast, P < 0.0001). The clinical efficacy of Ritalin LA is not influenced by breakfast and works independently of food intake.

Intracortical motor inhibition and facilitation in adults with attention deficit/hyperactivity disorder.

Using transcranial magnetic stimulation (TMS), disturbed facilitatory and inhibitory motor functions were recently found to correlate with motor hyperactivity in children with ADHD. Since hyperactivity seems to become reduced in ADHD during the transition to adulthood, a normalization of motor cortical excitability might be assumed. Therefore, we investigated the same inhibitory and facilitatory TMS paradigms in ADHD adults as we had previously examined in children. Motor cortical excitability was tested with TMS paired-pulse protocols in 21 ADHD adults and 21 age- and gender-matched healthy controls. In contrast to our results in ADHD children, no group-specific differences in amplitude changes of motor evoked potentials for inhibitory inter-stimulus intervals (ISI) (3, 100, 200 and 300 ms) or for facilitatory ISIs (13, 50 ms) could be detected. In ADHD adults, disturbed facilitatory and inhibitory motor circuits as found in ADHD children could not be shown, probably due to a development-dependent normalization of motor cortical excitability.

Impaired transcallosally mediated motor inhibition in adults with attention-deficit/hyperactivity disorder is modulated by methylphenidate.

Using transcranial magnetic stimulation (TMS) in children with ADHD, an impaired transcallosally mediated motor inhibition (ipsilateral silent period, iSP) was found, and its restoration was correlated with improvement of hyperactivity under medication with methylphenidate (MPH). Hyperactivity has been reported to decrease during transition into adulthood, although some motor dysfunction might persist. As one underlying neurophysiological process, a development-dependent normalization of motor cortical excitability might be postulated. In order to test this hypothesis, we measured the iSP in 21 adult ADHD patients and twenty-one sex- and age-matched healthy controls. In 16 of these patients, a second TMS was performed under treatment with MPH. Our results indicate a persistence of impaired transcallosally mediated motor cortical inhibition (shortened duration) in ADHD adults, which was correlated with clinical characteristics of hyperactivity and restlessness, and was restored by MPH. In contrast to ADHD in childhood, the iSP latency was not impaired, suggesting a partial development-dependent normalization of motor cortical excitability in ADHD adults. ISP duration appears to be a sensitive parameter for the assessment of disturbed intercortical inhibition in adults with ADHD.

Restoration of disturbed intracortical motor inhibition and facilitation in attention deficit hyperactivity disorder children by methylphenidate.

BACKGROUND: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far. METHODS: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score. RESULTS: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec). CONCLUSIONS: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement.

Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours: discontinuation study.

We investigated the effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities by randomly withdrawing it after a 6-week period of open treatment. Of the 49 patients responding to the treatment, 39 took part in a randomised withdrawal trial. The placebo subgroup (n=20) showed more aggressive behaviour as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale than did the continuing subgroup (n=19). The results indicate that discontinuation of zuclopenthixolin this population leads to an increase in aggressive behaviour.

Manual treatment effects to the upper cervical apophysial joints before, during, and after endotracheal anesthesia: a placebo-controlled comparison.

OBJECTIVES: In this preliminary, placebo-controlled clinical trial, two different manual treatments were compared, spinal manipulation and postisometric relaxation, for dysfunctional motion segments of the upper cervical spinal column. The influence of the muscular portion on the joint-play restriction of a motion segment can be ignored in anesthesia, and the manual evaluation of this joint-play restriction must be focused on nonmuscular structures. By retesting in anesthesia, it is possible to examine whether mobilization and manipulation affect exclusively the muscular structures or also affect the other parts of the motion segment. Conclusions can be drawn about the superiority of one or both treatments and about the structural basis of the restricted joint play and its palpation. DESIGN: A total of 26 inpatients at the surgical or orthopedic department of the University of Rostock were examined manually at four testing times: before and after manual treatment, in anesthesia, and within 24 hrs of completing anesthesia. They were randomized into three groups: postisometric relaxation (mobilization), spinal manipulation (thrust technique), and placebo. RESULTS: A highly significant effect for both treatments was found posttherapeutically (P < 0.01) but not for placebo. In anesthesia, the treatment effect of spinal manipulation was further significant (P < 0.01) when compared with placebo. For postisometric relaxation, however, it was not (P = 0.160). A significant difference between spinal manipulation and postisometric relaxation was not found in anesthesia (P = 0.137). The treatment effect postnarcotically was further significant when compared with placebo only for spinal manipulation (P = 0.011). CONCLUSIONS: Both treatments are superior to placebo. Postisometric relaxation seems to affect mainly the muscular parts of the treated segments and less so the other parts, such as the joint capsule or the segmental affiliated ligaments and fascia. Spinal manipulation seems to influence all other segmental parts more effectively, and the treatment effect persists longer. A joint-play restriction cannot be an exclusively muscular tension phenomenon. Segmental motion dysfunctions show a high variability in their spontaneous course.