Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

[Hypnotics--state of the science]. / Hypnotika--Stand der Forschung.

This article provides an overview of the indications and effects of sleep-inducing drugs. Pharmacological treatment should only be considered in cases of insufficient response to non-pharmacological interventions. Benzodiazepines and benzodiazepine receptor agonists are indicated for the short-term treatment of acute insomnia. Due to the risk of tolerance and dependency, sedative antihistamines and antidepressants are widely used as long-term hypnotics. Other substances, including herbal compounds and melatonin have few side effects; however, the therapeutic efficacy is very limited. Currently, long-term data on the efficacy and tolerability of sleep-inducing substances are lacking. Specifically in cases of non-response to first line treatment, extended psychiatric and somatic evaluation and treatment of associated disorders are recommended.

Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: Pooled analysis of two randomized controlled studies.

OBJECTIVES: Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modulation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic approach for chronic tinnitus. METHODS: Two randomized, double-blind, parallel-group, controlled clinical trials were performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10 stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex. RESULTS: rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal and temporal rTMS (43%), as compared to sham (6%). CONCLUSIONS: This large study demonstrates the safety and tolerability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo, secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal and temporal rTMS protocol.

Effects of acupuncture needle penetration on motor system excitability.

OBJECTIVES: Transcranial magnetic stimulation (TMS) studies reported changes in motor evoked potential amplitude after acupuncture needling both at traditional acupoints and non-acupoints. However, the effects of needle penetration per se have not yet been investigated with TMS. The present study aimed at exploring effects of deep manual acupuncture needling compared to a state-of-the-art, non-penetrating control condition on several standard TMS measures of motor system excitability. METHODS: Twenty healthy volunteers received both verum and sham acupuncture applied at the acupoint GB 34 near the right knee, using a crossover design. A needle with a retractable tip ("Streitberger needle") was used as sham condition to minimize non-specific effects. TMS parameters (resting motor threshold, active motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation) were calculated from the abductor digiti minimi (ADM) of both hands 15 min before and after needling by a researcher blind to the treatment condition. RESULTS: Verum compared to sham acupuncture significantly increased resting motor threshold. No significant treatment effect was found for any other measure, though cortical silent period and intracortical facilitation showed trends to increase in the hemisphere contralateral to the needling site after verum acupuncture. CONCLUSIONS: These results suggest a subtle but specific inhibitory effect of acupuncture needle penetration at acupoint GB 34 on motor system excitability. Further investigations should be performed with a particular emphasis on the measurements of resting motor threshold, cortical silent periods and intracortical facilitation.

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (­18 min (P = 0.02)) and WASO (­54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

[Hypothermia under olanzapine treatment: clinical case series and review of current literature]. / Hypothermie unter Olanzapin : Eine Fallserie mit Literaturübersicht.

BACKGROUND: Antipsychotic drugs may lead to hypothermia as well as hyperthermia. Although known for decades and clinically highly relevant, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are still far from being fully understood. In clinical practice, much attention is paid to antipsychotic drug-induced elevation of body core temperature as observed in the neuroleptic malignant syndrome (NMS). But also hypothermia is a clinically highly relevant adverse reaction to antipsychotic drugs. MATERIAL AND METHODS: Here we report a case series of three patients who developed severe hypothermia after administration of olanzapine. A review of the current literature is given with a focus on risk factors for the development of antipsychotic drug-induced hypothermia and its pathophysiologic mechanisms. RESULTS: A 51-year-old female patient suffering from catatonic schizophrenia, cachectic nutritional condition and hypothyroidism developed severe hypothermia of 30.0°C body core temperature after administration of 30 mg olanzapine per day under comedication with lorazepam and L-thyroxine. A 48-year-old female patient with catatonic schizophrenia showed hypothermia of 31.0°C (rectal measurement) after single-dose administration of olanzapine 10 mg orally and a total of 3 mg lorazepam (1-1-1 mg). The third case report describes a 69-year-old male patient with acute delusional disorder exhibiting hypothermia of 33.0°C (rectal measurement) in combination with a reversible atrioventricular block grade III without any further comedication. CONCLUSION: A review of the current literature reveals that thermoregulatory disturbances as sequelae of antipsychotic drug administration depend on individual disposition as well as various independent risk factors such as environmental temperature, somatic comorbidities, endocrinological abnormalities (e.g. hypothyroidism) and structural damage of the brain. A complex interaction of dopaminergic regulatory mechanisms in the ventral hypothalamus and peripheral vaso- and sudomotor adjustments seems to be causative. Hypothermia following antipsychotic drug administration represents a serious adverse drug reaction and a potentially life-threatening event.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

rTMS for the treatment of tinnitus: the role of neuronavigation for coil positioning.

Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Both animal models and functional imaging data in tinnitus patients suggest that tinnitus is associated with increased neuronal activity, increased synchronicity and functional reorganisation in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus. Repetitive transcranial magnetic stimulation (rTMS), a non invasive method for modulation of cortical activity, has been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been used to transiently interfere with the intensity of tinnitus. Repeated sessions of low-frequency rTMS have been investigated as a treatment for tinnitus. Here, we review data from clinical trials and discuss potential neurobiological mechanisms with special focus on the relevance of the stimulation target and the method of TMS coil positioning. Different functional neuroimaging techniques are used for detecting tinnitus-related changes in brain activity. They converge in the finding of increased neuronal activity in the central auditory system, but they differ in the exact localisation of these changes, which in turn results in uncertainty about the optimal target for rTMS treatment. In this context, it is not surprising that the currently available studies do not demonstrate clear evidence for superiority of neuronavigational coil positioning. Further development of rTMS as a treatment for tinnitus will depend on a more detailed understanding of both the neuronal correlates of the different forms of tinnitus and of the neurobiological effects mediating the benefit of TMS on tinnitus perception.

Left temporal low-frequency rTMS for the treatment of tinnitus: clinical predictors of treatment outcome--a retrospective study.

BACKGROUND: There is increasing evidence that repetitive transcranial magnetic stimulation (rTMS) can reduce chronic tinnitus. However, treatment results are characterized by high interindividual variability. Therefore, the identification of predictors for treatment response is of high clinical relevance. METHODS: Clinical data of 194 patients with tinnitus were evaluated. All patients were treated with a standardized rTMS procedure (1 Hz, 10 days, 2000 stimuli/day, over the left temporal cortex). A potential influence on the outcome was analysed for the following parameters: age, gender, depression scores in Beck Depression Inventory (BDI) and tinnitus severity (TQ) before rTMS, lateralization, frequency and duration of tinnitus and extent of hearing loss. RESULTS: An effect of tinnitus laterality was observed. In patients with left-sided or bilateral tinnitus, rTMS resulted in a statistically significant reduction of TQ scores, whereas patients with right-sided tinnitus did not show a significant improvement after rTMS treatment. However, in correlation analyses, we found a trend which did not reach statistical significance that in the subgroup of treatment responders tinnitus duration influenced rTMS outcome. In addition, a multiple regression analysis identified the TQ score at baseline as a significant predictor for treatment outcome. For all other investigated parameters, no statistically significant effects were found. CONCLUSIONS: This study suggests that left temporal low-frequency rTMS has beneficial effects in left-sided and bilateral tinnitus, but not in right-sided tinnitus. In line with the results from earlier studies involving smaller samples, tinnitus duration was found to influence rTMS outcome.

[Frontotemporal dementia in association with a family history of dementia and ApoE polymorphism]. / Frontotemporale Demenz im Zusammenhang mit Familienanamnese Demenz und ApoE-Genotyp.

OBJECTIVE: To examine the association between apolipoprotein E (ApoE) and a family history of dementia in 1st- and 2nd-degree relatives of patients with frontotemporal dementia (FTD) with a dementia onset by age 70. METHODS: The study included 494 dementia patients (73 FTD patients) and 82 cognitively normal spousal control subjects. Neuropsychiatric examination, Consortium To Establish a Registry on Alzheimer's Disease (CERAD) testing, the clock-drawing test, and ApoE genotyping were performed in patients and controls. All patients were examined by magnetic resonance imaging. FTD patients fulfilled the Lund-Manchester criteria. RESULTS: All controls had normal Mini Mental State exam (MMSE > or =27). 28 of the 82 spousal controls were excluded because CERAD test results were consistent with the diagnosis of mild cognitive impairment (MCI) or the CERAD was incomplete. The remaining 54 spousal controls had CERAD test results with z-scores >/= -1.5. The number of dementia patients with FTD was 73. Apo epsilon4 homozygosity was found in 13.6% of the FTD patients. None of the spousal controls was homozygous for the Apo epsilon4 genotype (p=0.005). A positive family history of dementia was lowest among cognitively normal spousal controls (9.3%). It rose to 35.6% for FTD patients and was highest among Apo epsilon4 homozygous FTD patients (50.0%). CONCLUSIONS: Apo epsilon4 homozygosity is associated with a family history of dementia and FTD in our cohort if the current clinical criteria are employed. It is likely that autopsy might reveal amyloid beta deposits typical for Alzheimer's disease among the Apo epsilon4 homozygous patients with frontotemporal clinical presentation and neuroimaging consistent with FTD. Apo epsilon4 homozygosity has not yet been defined as an exclusion criterion for the diagnosis of FTD. In the future, a revision of the clinical criteria should consider the ApoE genotype.

Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1.

BACKGROUND AND PURPOSE: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood-brain barriers (BBB) is currently unknown. EXPERIMENTAL APPROACH: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. KEY RESULTS: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. CONCLUSIONS AND IMPLICATIONS: Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled, randomized multicenter study.

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

[Insomnias: I. Aetiology, pathophysiology and diagnostics]. / Insomnien: I. Atiologie, Pathophysiologie und Diagnostik.

Difficulties to initiate or maintain sleep, early morning awakening and resulting impairment of daytime functioning are a frequent comorbidity of many psychiatric and medical disorders. The so-called primary or psychophysiological insomnia as a distinct independent form of insomnia is a far less frequent condition. This article gives an overview of the diagnostic process for insomniac disorders. Furthermore, up to date neurobiological models of insomnia are discussed.

Modulating cerebello-thalamocortical pathways by neuronavigated cerebellar repetitive transcranial stimulation (rTMS).

OBJECTIVES: Increasing evidence suggests that dysfunctions of the cortico-cerebello-thalamocortical circuit are involved in the pathophysiology of neuropsychiatric disorders. This study explores the effects of cerebellar repetitive transcranial magnetic stimulation (rTMS) on cerebello-thalamocortical pathways. METHODS: Ten healthy volunteers received MRI-guided rTMS in four separate sessions (120% motor threshold, 1000 stimuli) over either the medial or the right lateral cerebellum using frequencies of 1 and 10 Hz. Motor cortex excitability was assessed before and after the intervention by paired-pulse transcranial magnetic stimulation. RESULTS: Depending on stimulation frequency, cerebellar rTMS differentially modified intracortical inhibition. Low frequency rTMS increased short intracortical inhibition (SICI), whereas high frequency rTMS had no significant effect on SICI. CONCLUSIONS: These results suggest that rTMS over the cerebellum can modulate cerebello-thalamocortical pathways in a frequency-specific manner.

[Documentation in psychiatry and psychotherapy: prerequisites and clinical practice]. / Dokumentation in der Psychiatrie und Psychotherapie: Rechtliche Grundlagen und klinische Praxis.

BACKGROUND: As a result of changes to the legal and economic framework over the past years, medical documentation has changed substantially. METHODS: Based on a literature search of important medicolegal studies and appeal decisions, an overview is given of legal principles and their practical consequences, especially for the fields of psychiatry and psychotherapy. RESULTS: Documentation is a contractual and crime-related duty arising from the professional code for doctors and the legal obligation to provide documentation. In addition to being a memory aide for the doctor, its purposes are to safeguard and justify the treatment and to provide legal evidence. The documentation should be provided in a format that is sufficiently clear for specialist staff, using keywords, possibly handwritten, and use contemporary terminology. All important diagnostic and therapeutic measures must be documented. This is particularly important when the treatment deviates from standard treatment and in medical procedures aiming to protect the patient. CONCLUSIONS: The legal requirements for documentation are becoming more stringent. The time spent on such activities has so far not been reimbursed by the financing bodies.