Implementing shared decision-making on acute psychiatric wards: a cluster-randomized trial with inpatients suffering from schizophrenia (SDM-PLUS).

AIMS: Although shared decision-making (SDM) has the potential to improve health outcomes, psychiatrists often exclude patients with more severe mental illnesses or more acute conditions from participation in treatment decisions. This study examines whether SDM is facilitated by an approach which is specifically adapted to the needs of acutely ill patients (SDM-PLUS). METHODS: The study is a multi-centre, cluster-randomised, non-blinded, controlled trial of SDM-PLUS in 12 acute psychiatric wards of five psychiatric hospitals addressing inpatients with schizophrenia or schizoaffective disorder. All patients fulfilling the inclusion criteria were consecutively recruited for the trial at the time of their admission to the ward. Treatment teams of intervention wards were trained in the SDM-PLUS approach through participation in two half-day workshops. Patients on intervention wards received group training in SDM. Staff (and patients) of the control wards acted under 'treatment as usual' conditions. The primary outcome parameter was the patients' perceived involvement in decision-making at 3 weeks after study enrolment, analysed using a random-effects linear regression model. RESULTS: In total, 161 participants each were recruited in the intervention and control group. SDM-PLUS led to higher perceived involvement in decision-making (primary outcome, analysed patients n = 257, mean group difference 16.5, 95% CI 9.0-24.0, p = 0.002, adjusted for baseline differences: ß 17.3, 95% CI 10.8-23.6, p = 0.0004). In addition, intervention group patients exhibited better therapeutic alliance, treatment satisfaction and self-rated medication compliance during inpatient stay. There were, however, no significant improvements in adherence and rehospitalisation rates in the 6- and 12-month follow-up. CONCLUSIONS: Despite limitations in patient recruitment, the SDM-PLUS trial has shown that the adoption of behavioural approaches (e.g. motivational interviewing) for SDM may yield a successful application to mental health. The authors recommend strategies to ensure effects are not lost at the interface between in- and outpatient treatment.Trial registration: The trial was registered at Deutsches Register Klinischer Studien (DRKS00010880).

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.

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.

[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.

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.

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.

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.

Cognitive and neurobiological alterations in electromagnetic hypersensitive patients: results of a case-control study.

BACKGROUND: Hypersensitivity to electromagnetic fields (EMF) is frequently claimed to be linked to a variety of non-specific somatic and neuropsychological complaints. Whereas provocation studies often failed to demonstrate a causal relationship between EMF exposure and symptom formation, recent studies point to a complex interplay of neurophysiological and cognitive alterations contributing to symptom manifestation in electromagnetic hypersensitive patients (EHS). However, these studies have examined only small sample sizes or have focused on selected aspects. Therefore this study examined in the largest sample of EHS EMF-specific cognitive correlates, discrimination ability and neurobiological parameters in order to get further insight into the pathophysiology of electromagnetic hypersensitivity. METHOD: In a case-control design 89 EHS and 107 age- and gender-matched controls were included in the study. Health status and EMF-specific cognitions were evaluated using standardized questionnaires. Perception thresholds following single transcranial magnetic stimulation (TMS) pulses to the dorsolateral prefrontal cortex were determined using a standardized blinded measurement protocol. Cortical excitability parameters were measured by TMS. RESULTS: Discrimination ability was significantly reduced in EHS (only 40% of the EHS but 60% of the controls felt no sensation under sham stimulation during the complete series), whereas the perception thresholds for real magnetic pulses were comparable in both groups (median 21% versus 24% of maximum pulse intensity). Intra-cortical facilitation was decreased in younger and increased in older EHS. In addition, typical EMF-related cognitions (aspects of rumination, symptom intolerance, vulnerability and stabilizing self-esteem) specifically differentiated EHS from their controls. CONCLUSIONS: These results demonstrate significant cognitive and neurobiological alterations pointing to a higher genuine individual vulnerability of electromagnetic hypersensitive patients.

Functional imaging of chronic tinnitus: the use of positron emission tomography.

Recent advances in functional imaging have opened new possibilities for understanding tinnitus. Especially, positron emission tomography (PET) has been increasingly used in the last two decades to identify cortical networks, which are involved in the generation of various forms of chronic tinnitus. PET studies have confirmed that the anatomical location of the anomalies that cause many forms of tinnitus are regions of the brain that are normally involved in auditory processing as well as regions engaged in emotional processing. These findings have contributed to the development of new more causally oriented treatment strategies. In particular, identification of increased activity of the auditory cortex by PET has prompted the use of focal brain stimulation techniques such as electrical or transcranial magnetic stimulation in treatment of tinnitus. PET studies that map distinct neurochemical pathways and receptors by the use of specific ligands may in the future provide new possibilities for pharmacologically based treatment of some forms of tinnitus.

TMS for treatment of chronic tinnitus: neurobiological effects.

Results of neurophysiological and neuroimaging studies suggest that some forms of chronic tinnitus can be regarded to be "hyperexcitability syndromes", caused by abnormal focal brain activity. Low frequency repetitive magnetic stimulation (rTMS) is an efficient method to selectively reduce the abnormally increased activity in distinct cortical areas. An increasing amount of clinical data suggest that low frequency rTMS might be an effective therapy that is directed at the cause of some forms of chronic tinnitus. To further explore the underlying neurobiological mechanisms we investigated the effect of rTMS on cortical excitability in healthy human subjects using the protocol, which has been successfully used for the treatment of tinnitus. We determined different parameters of motor cortex excitability (resting motor threshold, RMT; active motor threshold, AMT; short intracortical inhibition, ICI; short intracortical facilitation, ICF; and the duration of the cortical silent period, CSP) before and after 5 days of low frequency rTMS (2000 stimuli/day at 110% of RMT) over the left auditory cortex. Five sessions of low frequency rTMS resulted in a significant prolongation of the CSP. All other signs of cortical excitability that we studied remained unchanged. These findings suggest, that low frequency rTMS may evoke long-term depression (LTD)-like effects resulting in enhancement of subcortical inhibition.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Transient changes in cortical distribution of S100 proteins during reorganization of somatotopy in the primary motor cortex induced by facial nerve transection in adult rats.

In adult rats, the primary motor cortex (MI) comprises a somatotopic map of muscle representations. This somatotopy is modified after transection of the facial nerve (N7x). Mapping with cortical stimulation revealed that the underlying cortical reorganization is biphasic. Primary changes cause a transient disinhibition of long cortico-cortical connections in both hemispheres. While the first reaction vanishes within a few hours, short intra-areal connections are disinhibited within MI contralateral to N7x. The resulting co-operation between adjacent parts of MI persists as long as peripheral reinnervation is prevented. Cellular mechanisms underlying this cortical reorganization are largely unknown. Here, we utilized changes in immunoreactivity of S100 proteins (S100-IR) known as a sensitive indicator of astroglial reactions during plastic reactions in the central nervous system. Within 1 h of N7x, zones with enhanced S100-IR appeared in both hemispheres. Between 3. 5 and 18 h, reaction patterns with changing topography were transiently prominent in many cortical areas including parts of MI which surrounded the facial muscle representation fields. After 24 h, the facial muscle representation contralateral to N7x became labelled while S100-IR enhancement disappeared in most of the cortex. S100-IR-enhancement vanished completely during the next day of survival. Data presented suggest that (i) enhancement of S100-IR labels cortical tissue during the functional reorganization that is induced by N7x, (ii) large parts of the cerebral cortex participate in the reorganization, before it is finally focused on the representation field of MI that corresponds with contralateral N7x, and (iii) temporo-spatial patterns of astrocytic reactions apparently play a role in the underlying plasticity reaction.

Rapid astroglial reactions in the motor cortex of adult rats following peripheral facial nerve lesions.

We report on changes in the motor cortex of adult rats that rapidly and transiently followed various types of facial nerve lesions. These reactions led to enhanced immunoreactivities of various astroglial markers: S-100 protein (a Ca2+- and Zn2+-binding protein predominantly located in the cytosol of astrocytes), glial fibrillary acidic protein (a cytoskeletal protein) and connexin 43 (the astroglial gap junction protein). Reactions could be visualized 1 h after the facial nerve lesion and disappeared within about 5 days after surgery. Combined lesions of the facial and trigeminal nerves modified the spatial pattern of the astroglial reaction, similar to intramuscular injections of botulinum toxin, which inhibits the release of acetylcholine in motor endplates. Data presented suggest that peripheral interference with muscular functions rapidly induces modifications in the motor cortex.

Electron microscopical evidence of synaptic reorganization in the contralateral motor cortex of adult rats following facial nerve lesion.

Here we report on the rapid changes in the motor cortex of the rat following peripheral lesioning of a motor nerve. Facial nerve transection increases synaptic reorganization (autophagy, lysosomal degradation of synaptic components) already within 4 h after lesion. These changes occur in the motor cortex of both hemispheres, i.e. on the same and contralateral sides. An increase in the number of presynaptic lysosomes was transient and returned to below normal values within 24 h after facial nerve transection.

Biphasic reorganization of somatotopy in the primary motor cortex follows facial nerve lesions in adult rats.

Effects of facial nerve transection were studied on muscle responses evoked by electrical stimulation in the primary motor cortex (MI) of adult rats. In intact animals, activated muscles varied according to the somatotopic representation map, and responses were restricted to the contralateral side. Unilateral transection of the facial nerve extinguished contralateral vibrissal responses, while ipsilateral vibrissae began to respond within 4 min. This abnormal response (primary change) was transient and gradually disappeared within hours to days. Instead, contralateral movements of forepaw and eye/eyelid muscles could be evoked from increasing portions of the former vibrissal field (secondary change), in which many points became unresponsive. After 4 days, the former vibrissal field had shrunk to a small central part, where ipsilateral vibrissae responsiveness remained. The secondary modification was stable for at least 2 weeks. Since the primary change is rapid, transient and may be mimicked by picrotoxin, it may be based on disinhibition of commissural connections, while the secondary change is longlasting and therefore may include some form of reorganization of associational synapses.

Purine seizure disorders.

Developing antiepileptic agents that are specifically tailored to a patient's individual biochemistry has long been a goal of neurology. Three patients who had hyperuricosuria combined with a seizure disorder that failed to respond to traditional anticonvulsants are described. The patients had the best control of their seizure disorder when a specific metabolic drug, allopurinol, was used as an anticonvulsant. All three patients had onset of the seizure disorder at 22 months of age, a finding possibly related to maturation of purine enzymes. Because elevated uric acid levels in the immediate postictal period may occur in seizure patients, the presence of an elevated uric acid clearance in seizure-free periods is needed to consider the diagnosis of an allopurinol-responsive seizure problem in any individual patient. In the two patients past the onset of puberty, lowering (one case) and cessation (other case) of the dose of allopurinol has been possible.