Insomnia disorder: clinical and research challenges for the 21st century.

BACKGROUND AND PURPOSE: Insomnia is a common and debilitating disorder that is frequently associated with important consequences for physical health and well-being. METHODS: An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field of insomnia and identified future priorities. RESULTS: The association of trajectories of insomnia with subsequent quality of life, health and mortality should be investigated in large populations. Prospective health economics studies by separating the costs driven specifically by insomnia and costs attributable to its long-term effects are needed. Ignoring the heterogeneity of insomnia patients leads to inadequate diagnosis and inefficient treatment. Individualized interventions should be promoted. More data are needed on both the impact of sleep on overnight effects, such as emotion regulation, and the potential compensatory effort to counteract diurnal impairments. Another gap is the definition of neurocognitive deficits in insomnia patients compared to normal subjects after chronic sleep loss. There are also a number of key gaps related to insomnia treatment. Expert guidelines indicate cognitive-behavioural therapy for insomnia as first-line treatment. They neglect, however, the reality of major healthcare providers. The role of combined therapy, cognitive-behavioural therapy for insomnia plus pharmacological treatment, should be evaluated more extensively. CONCLUSION: Whilst insomnia disorder might affect large proportions of the population, there are a number of significant gaps in the epidemiological/clinical/research studies carried out to date. In particular, the identification of different insomnia phenotypes could allow more cost-effective and efficient therapies.

Cognitive remediation for depressed inpatients: Results of a pilot randomized controlled trial.

OBJECTIVE: Neurocognitive deficits that persist despite antidepressive treatment and affect social and vocational functioning are well documented in major depressive disorder. Cognitive training approaches have proven successful in ameliorating these deficits in other psychiatric groups, but very few studies have been conducted in unipolar depressive patients by now. In contrast to previous studies solely including outpatients, effects of a cognitive remediation intervention on neurocognitive functioning of depressed inpatients were assessed by the present study. METHOD: A randomized controlled trial was carried out with 46 depressed inpatients of a psychiatric hospital. Patients were randomly assigned to either a control group that received standard drug and non-drug (cognitive behavioural, occupational, sports, relaxation and music therapy) antidepressive treatment or a remediation group that additionally received 12 sessions of cognitive training for a total of 4 weeks (three sessions per week). An intent to treat analysis and a last observation carried forward method was used for data analyses. RESULTS: Patients of the remediation group demonstrated greater improvements in neurocognitive measures of verbal and nonverbal memory, working memory and executive function (Cohen's d effect sizes between .52 and .98). CONCLUSIONS: These results provide preliminary evidence that cognitive remediation interventions can be successfully applied also in psychiatric inpatients experiencing an acute depressive episode.

Cognitive remediation improves cognition and good cognitive performance increases time to relapse--results of a 5 year catamnestic study in schizophrenia patients.

BACKGROUND: Cognitive deficits are stable features of schizophrenia that are linked to functional outcome. Cognitive remediation approaches have been proven successful in ameliorating these deficits, although effect sizes vary considerably. Whether cognitive deficits are serious predictors of clinical outcome is less clear. METHODS: Sixty patients suffering from schizophrenia were included in our sample, thirty of them received computer-assisted cognitive training, and thirty received occupational therapy. For a subsample of 55 patients, who could be traced over a period of five years after the end of the cognitive remediation intervention, time until first relapse and time in psychosis were determined retrospectively from their medical records. RESULTS: Cognitive remediation significantly improved problem solving, memory and attention with high effect sizes. Employment status, a post test verbal memory performance measure and a measure of executive functioning outperformed all other measures in the prediction of time to relapse, while allocation to treatment group outperformed all other variables in the prediction of both cognitive measures. CONCLUSIONS: Cognitive remediation of neurocognitive deficits thus makes sense in a twofold fashion: It enhances cognition directly and positively acts on clinical course indirectly via improved neurocognition. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004880.

Determinants of depressive symptoms in narcoleptic patients with and without cataplexy.

The present prospective study assesses depressive symptoms in narcoleptic patients with (NC+) and without (NC-) cataplexy (46 women, 40 men) and age- and sex- matched healthy controls. Seventy patients were under treatment with stimulants and/or anticataplectics. All subjects completed the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale (SDS), the Global Impression of Severity of Depression (GSD), the Profile of Mood States (POMS) and Epworth Sleepiness Scale. Patients with narcolepsy were more depressed than controls (higher scores in BDI, GSD, SDS, and POMS [in the total score and in all subscale scores]); however, between the NC+ and NC- patient groups, no differences were found. Our study shows that the women and the patients using antidepressants and stimulants (combination) have a higher probability for depressive symptoms independent of the presence of cataplexy. The lack of difference between NC+ and NC- in the level of depression supports the assumption that the major psychosocial burden in narcolepsy is not necessarily associated with the presence of cataplexy.

Reliability and validity of the brief insomnia questionnaire in the America insomnia survey.

STUDY OBJECTIVES: to evaluate the reliability and validity of the Brief Insomnia Questionnaire (BIQ), a fully structured questionnaire developed to diagnose insomnia according to hierarchy-free Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), International Classification of Diseases-10 (ICD-10), and research diagnostic criteria/International Classification of Sleep Disorders-2 (RDC/ICSD-2) general criteria without organic exclusions in the America Insomnia Survey (AIS). DESIGN: probability subsamples of AIS respondents, oversampling BIQ positives, completed short-term test-retest interviews (n = 59) or clinical reappraisal interviews (n = 203) to assess BIQ reliability and validity. SETTING: the AIS is a large (n = 10,094) epidemiologic survey of the prevalence and correlates of insomnia. PARTICIPANTS: adult subscribers to a national managed healthcare plan. INTERVENTION: None MEASUREMENTS AND RESULTS: BIQ test-retest correlations were 0.47-0.94 for nature of the sleep problems (initiation, maintenance, nonrestorative sleep [NRS]), 0.72-0.95 for problem frequency, 0.66-0.88 for daytime impairment/distress, and 0.62 for duration of sleep. Good individual-level concordance was found between BIQ diagnoses and diagnoses based on expert interviews for meeting hierarchy-free inclusion criteria for diagnoses in any of the diagnostic systems, with area under the receiver operating characteristic curve (AUC, a measure of classification accuracy insensitive to disorder prevalence) of 0.86 for dichotomous classifications. The AUC increased to 0.94 when symptom-level data were added to generate continuous predicted-probability of diagnosis measures. The AUC was lower for dichotomous classifications based on RDC/ICSD-2 (0.68) and ICD-10 (0.70) than for DSM-IV-TR (0.83) criteria but increased consistently when symptom-level data were added to generate continuous predicted-probability measures of RDC/ICSD-2, ICD-10, and DSM-IV-TR diagnoses (0.92-0.95). CONCLUSIONS: these results show that the BIQ generates accurate estimates of the prevalence and correlates of hierarchy-free insomnia in the America Insomnia Survey.

The Tinnitus Research Initiative (TRI) database: a new approach for delineation of tinnitus subtypes and generation of predictors for treatment outcome.

Tinnitus, the phantom perception of sound, is a frequent disorder that causes significant morbidity and treatment is elusive. A large variety of different treatment options have been proposed and from most of them some patients benefit. However, a particular treatment that helps one patient may fail for others. This suggests that there are different forms of tinnitus which differ in their pathophysiology and their response to specific treatments. Therefore, it is a major challenge for tinnitus treatment to identify the most promising therapy for a specific patient. However, most published clinical treatment studies have enrolled only relatively small patient samples, making it difficult to identify predictors of treatment response for specific approaches. Furthermore, inter-study comparability is limited because of varying methods of tinnitus assessment and different outcome parameters. Performing clinical trials according to standardized methodology and pooling the data in a database should facilitate both clinical subtypisation of different forms of tinnitus, and identification of promising treatments for different types of tinnitus. This would be an important step towards the goal of individualized treatment of tinnitus.For these reasons, an international database of tinnitus patients, who undergo specific treatments, and are assessed during the course of this treatment with standardized instruments (e.g., psychoacoustic measures, questionnaires) has been established. The primary objectives of this database are (1) collecting a standardized set of data on patient characteristics, treatments, and outcomes from tinnitus patients consulting specialized tinnitus clinics all over the world (at present 13 centers in 8 countries), (2) delineating different subtypes of tinnitus based on data that has been systematically collected and (3) identifying predictors for individual treatment response based on the clinical profile. Starting in 2008, the database currently contains data from more than 400 patients. It is expected that more centers will join the project and that the patient numbers will rapidly grow, so that this international database will further facilitate future research and contribute to the development of evidence based on individualized treatment.

Cytochrome P450 2C19 inhibitory activity of common berry constituents.

The cytochrome P450 enzyme CYP2C19 is involved in the metabolism of many commonly prescribed drugs, including proton pump inhibitors, antiepileptics and antidepressants. CYP2C19 inhibitors from food and food supplements may augment the toxicity of these agents and lead to noncompliance with treatment. The present investigation addresses CYP2C19 inhibition by 18 berry constituents using a chemiluminescent assay. Test compounds displayed inhibitory properties in a concentration-dependent fashion, with IC(50) values ranging from 20.2 microM up to >316 microM. In the order of decreasing effect size, anthocyanidins were followed by anthocyanidin-monoglycosides and procyanidins. Anthocyanidin-diglucosides exhibited weak and biphasic effects. When compared with the CYP2C19 inhibitor fluvoxamine, the flavonoids under study were 50- to 750-fold less potent. It is concluded that the above natural substances are moderate to poor inhibitors of CYP2C19 in vitro.

Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension.

STUDY OBJECTIVES: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. METHODS: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. RESULTS: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P < .0001) at months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. CONCLUSIONS: Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919.

Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas.

Tinnitus, the phantom perception of sound, is a frequent disorder that causes significant morbidity. The pathophysiological mechanisms involved in tinnitus generation are still under exploration. Electrophysiological and functional neuroimaging studies give increasing evidence for abnormal functioning both within the central auditory system and in non-auditory brain areas. However, observed changes show great variability, hence lacking a conclusive picture. Recently, structural alterations in the central nervous system have been detected in tinnitus patients by voxel-based morphometry (VBM). Here we aimed to replicate these findings in an independent study sample. We performed structural MRI scans in 28 tinnitus patients with normal audiometry and used VBM to compare results with a control group, matched for age, sex and hearing status. As major results we found significant grey matter decreases in the tinnitus group in the right inferior colliculus and in the left hippocampus. However, neither changes in the subcallosal area nor in the thalamus as described recently have been observed. Our results underscore that (1.) VBM allows to detect structural alterations in tinnitus patients, which seem to be related to tinnitus pathophysiology. (2.) Both, areas in the auditory and the limbic system are involved giving further evidence for the important role of the limbic system in the pathophysiology of tinnitus. (3.) Even groups with similar clinical characteristics might differ in the underlying neurobiological changes.

sPhospholipase A(2) is inhibited by anthocyanidins.

Epidemiological studies suggest that nutritional antioxidants may reduce the incidence of neurodegenerative disorders and age-related cognitive decline. Specifically, protection against oxidative stress and inflammation has served as a rationale for promoting diets rich in vegetables and fruits. The present study addresses secretory phospholipase A(2) (sPLA(2)) as a novel candidate effector of neuroprotection conferred by anthocyanins and anthocyanidins. Using a photometric assay, 15 compounds were screened for their ability to inhibit PLA(2). Of these, cyanidin, malvidin, peonidin, petunidin, and delphinidin achieved K(i) values

Berry anthocyanins and their aglycons inhibit monoamine oxidases A and B.

Monoamine oxidases (MAO) are mitochondrial enzymes that catalyze the oxidation of monoamines in multiple tissues, including the brain. Elevated MAO activity has long been implicated in the etiology of depression, anxiety, and neurodegenerative disease, fuelling the search for inhibitors in the prevention and treatment of these disorders. We hypothesized that emerging neuroprotective effects of anthocyanins from berry fruits may be explained by an affinity of these polyphenols for MAO isoforms A or B. Using a luminometric MAO assay, 25 anthocyanidins, anthocyanidin-3-glycosides, anthocyanidin-3,5-diglucosides, proanthocyanidins, and phenolic metabolites were examined. For MAO A and B, IC(50) values in the low micromolar range were reached by anthocyanidins and anthocyanidin-3-glycosides, as opposed to values in the low millimolar range for phenolic acids. Kinetic analyses, performed with cyanidin and cyanidin-3-glucoside, indicated a competitive interaction of cyanidin with MAO A plus a mixed competitive and non-competitive mode of interaction of cyanidin with MAO B and of cyanidin-3-glucoside with both enzyme isoforms. Thus anthocyanins and their aglycons achieve MAO inhibition in vitro that is compatible with central nervous functionalities. For extrapolation of the present findings to in vivo effects, future studies will need to address in more detail the bioavailability of these dietary constituents.

Anthocyanins and anthocyanidins are poor inhibitors of CYP2D6.

The cytochrome P450 CYP2D6 isoform is involved in the metabolism of about 50% of all psychoactive drugs, including neuroleptic agents, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors and tricyclic antidepressants. Therefore, inhibition of cytochrome P450 activity by foodstuffs has implications for drug safety. The present study addresses inhibitory effects of polyphenolic anthocyanins and their aglycons that are found in many dietary fruits and vegetables. Using a chemiluminescent assay, we obtained IC(50) values ranging from 55 microM to > 800 microM for 17 individual compounds. According to earlier data on furanocoumarins from grapefruit extract, CYP2D6 inhibition is achieved in the range of 190-900 nM. As the tested anthocyanins and anthocyanidins were shown to be about 1,000-fold less potent, they are unlikely to interfere with drug metabolism by CYP2D6. Further studies are warranted to examine the effects of the above flavonoids on other CYP isoforms for more detailed toxicity profiles.

Inhibition of proteasome activity by anthocyanins and anthocyanidins.

Recent reports have demonstrated multiple benefits associated with the consumption of berry fruits, including a decreased vulnerability to oxidative stress, reduced ischemic brain damage, protection of neurons from stroke-induced damage and the reversal of age-related changes in brain and behaviour. Berry fruits contain high amounts of anthocyanins, which play a major role as free radical scavengers. The present study addresses proteasome inhibition as a further mechanism by which anthocyanins and their aglycons, the anthocyanidins, may exert health-promoting effects. HL-60 cells were incubated with 19 test substances and inhibition of the chymotrypsin-like enzyme activity was determined in a chemiluminescent assay. Anthocyanins and their aglycons achieved IC(50) values ranging from 7.8 microM for kaempferidinidin and pelargonidin, to 32.4 microM for delphinidin. Thus proteasome inhibitory properties of anthocyanins may contribute to their known anticarcinogenic, antioxidative, anti-inflammatory and neuroprotective activities, rationalizing dietary supplementations with anthocyanins in the prevention and treatment of chronic diseases, including neurodegenerative disorders.

Design of a placebo-controlled, randomized study of the efficacy of repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus.

BACKGROUND: Chronic tinnitus is a frequent condition, which can have enormous impact on patient's life and which is very difficult to treat. Accumulating data indicate that chronic tinnitus is related to dysfunctional neuronal activity in the central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method which allows to focally modulate neuronal activity. An increasing amount of studies demonstrate reduction of tinnitus after repeated sessions of low-frequency rTMS and indicate that rTMS might represent a new promising approach for the treatment of tinnitus. However available studies have been mono-centric and are characterized by small sample sizes. Therefore, this multi-center trial will test the efficacy of rTMS treatment in a large sample of chronic tinnitus patients. METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind multi-center trial of two weeks 1 Hz rTMS-treatment in chronic tinnitus patients. Eligible patients will be randomized to either 2 weeks real or sham rTMS treatment. Main eligibility criteria: male or female individuals aged 18-70 years with chronic tinnitus (duration > 6 months), tinnitus-handicap-inventory-score > or = 38, age-adjusted normal sensorineural hearing (i.e. not more than 5 dB below the 10% percentile of the appropriate age and gender group (DIN EN ISO 7029), conductive hearing loss < or = 15dB. The primary endpoint is a change of tinnitus severity according to the tinnitus questionnaire of Goebel and Hiller (baseline vs. end of treatment period). A total of 138 patients are needed to detect a clinical relevant change of tinnitus severity (i.e. 5 points on the questionnaire of Goebel and Hiller; alpha = 0.05; 1-beta = 0.80). Assuming a drop-out rate of less than 5% until the primary endpoint, 150 patients have to be randomized to guarantee the target number of 138 evaluable patients. The study will be conducted by otorhinolaryngologists and psychiatrists of 7 university hospitals and 1 municipal hospital in Germany. DISCUSSION: This study will provide important information about the efficacy of rTMS in the treatment of chronic tinnitus. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89848288.

Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study.

OBJECTIVES: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a new treatment strategy for patients with chronic tinnitus. However, functional abnormalities in tinnitus patients also involve brain structures used for attentional and emotional processing, such as the dorsolateral prefrontal cortex. Therefore, we have developed a new rTMS treatment strategy for tinnitus patients that consists of a combination of high-frequency prefrontal and low-frequency temporal rTMS. STUDY DESIGN: A total of 32 patients received either low-frequency temporal rTMS or a combination of high-frequency prefrontal and low-frequency temporal rTMS. Treatment effects were assessed with a standardized tinnitus questionnaire (TQ). RESULTS: Directly after therapy there was an improvement of the TQ-score for both groups, but no differences between groups. An evaluation after 3 months revealed a remarkable benefit from the use of combined prefrontal and temporal rTMS treatment. CONCLUSION: These results support recent data that suggest that auditory and nonauditory brain areas are involved in tinnitus pathophysiology.

Which tinnitus patients benefit from transcranial magnetic stimulation?

OBJECTIVES: Chronic tinnitus is associated with hyperactivity of the central auditory system. Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a treatment for chronic tinnitus. This study determined the factors that predict a beneficial outcome with rTMS treatment. STUDY DESIGN: Forty-five patients with chronic tinnitus underwent 10 sessions of low-frequency rTMS to their left auditory cortex. The treatment outcome was assessed with a tinnitus questionnaire. Therapeutic success was related to the patients' clinical characteristics. RESULTS: A significant reduction in tinnitus complaints occurred after rTMS. In the questionnaire, 40% of the patients improved by five points or more. Treatment responders were characterized by shorter duration of tinnitus complaints and no hearing impairment. CONCLUSION: Tinnitus-related neuroplastic changes might be less pronounced in patients with normal hearing and a short history of complaints. This could explain why those patients benefitted more from rTMS treatment.

Evidence of a role for the 5-HTTLPR genotype in the modulation of motor response to antidepressant treatment.

RATIONALE: Serotonergic mechanisms are thought to play an important role in the regulation of mood, motor activity and sleep patterns. Serotonin reuptake is controlled by the serotonin transporter (5-HTT) and by a common functional insertion/deletion polymorphism in the corresponding gene's promoter region (5-HTTLPR). Homozygosity for the long variant may confer a favourable response to treatment with serotonin reuptake inhibitors (SSRIs), and to sleep deprivation. OBJECTIVES: The study assessed the role of the 5-HTTLPR genotype in determining motor side effects of antidepressant medication. METHODS: Motor activity patterns of 62 patients with major depression who were being treated with either SSRIs or tricyclic antidepressants (TCAs) were monitored over a 24-h period using a wrist-actograph. Additionally, motor activity was rated in a semi-structured interview using the motor agitation and retardation scale (MARS). RESULTS: Night-time motor activity was significantly increased in homozygous carriers of the long 5-HTTLPR allele (LL-genotype) who were being treated with SSRIs in comparison to short allele carriers (LS-genotype and SS-genotype), regardless of the type of antidepressant treatment (P<0.001). It was also significantly increased in comparison to patients with the LL-genotype who were being treated with TCAs (P<0.01). Differences in actographic motor activity were most prominent between 11 p.m. and 4 a.m. Clinical ratings of motor activity also showed a trend toward higher agitation scores in patients with the LL-genotype who received SSRI treatment. CONCLUSIONS: Homozygosity for the long variant of the 5-HTTLPR may cause a predisposition to increased night-time motor activity in conjunction with SSRI treatment.

Performance of diadochokinetic movements in schizophrenic patients.

Motor deficits are common and disabling symptoms in schizophrenic patients, which have enormous impact on the long-term outcome of the disease by affecting work performance and daily functioning. They are attributed to the disorder itself, as well as to treatment with dopamine-blocking antipsychotics. This study assessed the kinematic parameters of motor performance of a diadochokinetic hand movement in 20 drug-naïve, 20 conventionally treated (haloperidol or fluphenazine), and 20 atypically treated (olanzapine) patients, as well as in 20 healthy controls using a three-dimensional ultrasonic movement analysis system. It also tested differences in motor enhancement as induced by an attentional strategy and in dexterity advantages of motor performance for the dominant hand between the four study groups. Amplitude and peak velocity of diadochokinetic hand movements were significantly reduced in all patient groups compared to the controls, while frequency of the repetitive movement remained unaffected. The reduction was most pronounced in the conventionally treated patients. In addition, movement automation was impaired, primarily under conventional antipsychotic treatment. The study also revealed weaker effects of an attentional enhancing strategy on the movement amplitude in atypically and conventionally treated patients compared to both controls and drug-naïve patients. Alterations of dexterity could not be detected either in the drug-naïve or in the treated patients. The results indicate that patients with schizophrenia suffer from a specific primary motor deficit in diadochokinesia with reduction of amplitude and peak velocity. This deficit is significantly worsened by conventional antipsychotic treatment. Antipsychotic treatment additionally reduces the enhancing effect of an attentional strategy on motor performance.

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus.

OBJECTIVES: The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low-frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability. STUDY DESIGN: Fusing of the individual PET-scan with the structural MRI-scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8-shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham-coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller). SETTING: Tertiary referral medical center. RESULTS: Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score. CONCLUSION: These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. METHODS: Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N = 17, sham coil with the TBS protocol). RESULTS: There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. CONCLUSIONS: This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies.