Philipp Sand

Association between A2a receptor gene polymorphisms and caffeine-induced anxiety.

The adenosine receptor system, which mediates the psychoactive effects of caffeine, is also thought to be involved in the regulation of anxiety. In this study, we examined the association between variations in anxiogenic responses to caffeine and polymorphisms in the A1 and A2a adenosine receptor genes. Healthy, infrequent caffeine users (N=94) recorded their subjective mood states following a 150 mg oral dose of caffeine freebase or placebo in a double-blind study. We found a significant association between self-reported anxiety after caffeine administration and two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymorphisms. Individuals with the 1976T/T and the 2592Tins/Tins genotypes reported greater increases in anxiety after caffeine administration than the other genotypic groups. The study shows that an adenosine receptor gene polymorphism that has been associated with Panic Disorder is also associated with anxiogenic responses to an acute dose of caffeine.

Prevalence of alcohol and drug abuse in schizophrenic inpatients

SummaryAll schizophrenic patients admitted consecutively either to the Psychiatric Hospital of the University of Munich (group 1,N=183) or the Mental State Hospital Haar/Munich (group 2,N=447) between 1.8.1989 and 1.2.1990 were examined to assess prevalence estimates for substance abuse in schizophrenic inpatients. psychiatric diagnosis were made according to ICD-9 criteria. Psychopathology and psychosocial variables were documented by means of the AMDP-protocol on admission and discharge. The diagnostic procedure included a detailed semi-structured interview concerning the individual alcohol and drug history and sociodemographic data, the Munich Alcoholism Screening Test (MALT), a physical examination and the screening of various laboratory parameters such as GGT and MCV, among others.The results show that substance abuse is a very common problem in schizophrenics. Lifetime prevalence rates for substance abuse were estimated at 21.8% in group 1 and 42.9% in group 2,3-month prevalence rates for substance abuse were estimated at 21.3% resp. 29.0%. Alcohol abuse was by far the most common type of abuse with prevalence estimates being 17.4% resp. 34.6%. Prevalence rates for substance abuse were much higher in the more “chronic” sample of the Mental State Hospital and in male patients. With respect to schizophrenic subtype few differences could be demonstrated with drug dependence being more common in patients with paranoid schizophrenia. The MALT proved to be a valuable sceening instrument for alcohol abuse in schizophrenics with both a high specifity and sensitivity. “Dual diagnosis” schizophrenics had a significantly higher rate of suicide attempts and were less likely to be married. Possible clinical implications of these findings are discussed.

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.

The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects

The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABAA/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (α1−3,5,6β2γ2S) indicating positive allosteric properties. Maximal stimulation at α1β2γ2S was observed with 10 μM hispidulin. In contrast to diazepam, hispidulin modulated the α6β2γ2S‐GABAA receptor subtype. When fed to seizure‐prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg−1 body weight (BW) per day) and diazepam (2 mg kg−1 BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood–brain barrier for the chemically synthesized, 14C‐labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (Kin) of 1.14 ml min−1 g−1, measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 μM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women.

Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. Pharmacological and genetic studies suggest that genes coding for proteins involved in the catecholaminergic system might be relevant for the pathogenesis of the disease. In the present study, we genotyped a single nucleotide polymorphism (472G/A=V158M) in the coding region of the catechol-O-methyl-transferase (COMT) gene in 115 patients with panic disorder and age- and sex-matched controls. Association analysis revealed a significant excess of the more active COMT allele (472G=V158) in patients with panic disorder (p=0.04), particularly in female patients (p=0.01), but not in male patients (p=1.0). The assessment of a possible interaction of the COMT polymorphism with a previously reported functional 30-bp VNTR in the monoamine oxidase A promoter (MAOALPR) in female patients did not yield significant results. Our data support a role of the 472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic disorder in women.

Association of a functional −1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia

Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.

The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus – first results from a PET study

Conclusion: Unilaterally increased metabolic activity within the primary auditory cortex (PAC) represents a robust finding in tinnitus patients. Targeting these hyperactive areas with image-guided low frequency repetitive transcranial magnetic stimulation (rTMS) results in subjective tinnitus reduction. More pronounced activation of the PAC predicted higher resistance to rTMS. Objectives: [18F]deoxyglucose (FDG)-positron emission tomography (PET) was used to assess metabolic activity within the central auditory system in tinnitus. The study investigated whether patterns of neuronal activity correlate with clinical features or may be used for the prediction of treatment outcome. Patients and methods: Twenty patients with chronic tinnitus underwent PET imaging followed by low frequency rTMS treatment. Neuroimaging data were compared with clinical parameters and treatment outcome. Results: PET data demonstrated an asymmetric activation of the central auditory system. Seventeen patients revealed increased activity of the primary auditory cortex on the left side, three on the right side. The extent of hypermetabolic activity prior to treatment correlated significantly with tinnitus reduction after rTMS, but not with clinical characteristics such as tinnitus severity, tinnitus laterality or tinnitus duration.

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.

Transcranial Magnetic Stimulation for the Treatment of Tinnitus: A New Coil Positioning Method and First Results

SummaryAuditory phantom perceptions are associated with hyperactivity of the central auditory system. Neuronavigation guided repetitive transcranial magnetic stimulation (rTMS) of the area of increased activity was demonstrated to reduce tinnitus perception. The study aimed at developing an easy applicable standard procedure for transcranial magnetic stimulation of the primary auditory cortex and to investigate this coil positioning strategy for the treatment of chronic tinnitus in clinical practice. The left gyrus of Heschl was targeted in 25 healthy subjects using a frameless stereotactical system. Based on individual scalp coordinates of the coil, a positioning strategy with reference to the 10--20-EEG system was developed. Using this coil positioning approach we started an open treatment trial. 28 patients with chronic tinnitus received 10 sessions of rTMS (intensity 110% of motor threshold, 1 Hz, 2000 Stimuli/day). Being within a range of about 20 mm diameter, the scalp coordinates for stimulating the primary auditory cortex allowed to determine a standard procedure for coil positioning. Clinical validation of this coil positioning method resulted in a significant improvement of tinnitus complaints (p<0.001). The newly developed coil positioning strategy may have the potential to offer a more easy-to-use stimulation approach for treating chronic tinnitus as compared with highly sophisticated, imaging guided treatment methods.

Controversy: Does repetitive transcranial magnetic stimulation/ transcranial direct current stimulation show efficacy in treating tinnitus patients?

BACKGROUND Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Functional imaging has demonstrated a relationship between the intensity of tinnitus and the degree of reorganization in the auditory cortex. Experimental studies have further shown that tinnitus is associated with synchronized hyperactivity in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus. METHODS Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive methods that can modulate cortical activity. These techniques have been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes. RESULTS Another approach that uses rTMS as a treatment for tinnitus is application of low-frequency rTMS in repeated sessions, to induce a lasting change of neuronal activity in the auditory cortex beyond the duration of stimulation. Beneficial effects of this treatment have been consistently demonstrated in several small controlled studies. However, results are characterized by high interindividual variability and only a moderate decrease of the tinnitus. The role of patient-related (for example, hearing loss, tinnitus duration, age) and stimulation-related (for example, stimulation site, stimulation protocols) factors still remains to be elucidated. CONCLUSIONS Even in this early stage of investigation, there is a convincing body of evidence that rTMS represents a promising tool for pathophysiological assessment and therapeutic management of tinnitus. Further development of this technique will depend on a more detailed understanding of the neurobiological effects mediating the benefit of TMS on tinnitus perception. Moreover clinical studies with larger sample sizes and longer follow-up periods are needed.