M. Brunovsky

Effect of Low-Frequency rTMS on Electromagnetic Tomography (LORETA) and Regional Brain Metabolism (PET) in Schizophrenia Patients with Auditory Hallucinations

Background: Auditory hallucinations are characteristic symptoms of schizophrenia with high clinical importance. It was repeatedly reported that low frequency (≤1Hz) repetitive transcranial magnetic stimulation (rTMS) diminishes treatment-resistant auditory hallucinations. A neuroimaging study elucidating the effect of rTMS in auditory hallucinations has yet to be published. Objective: To evaluate the distribution of neuronal electrical activity and the brain metabolism changes after low-frequency rTMS in patients with auditory hallucinations. Methods: Low-frequency rTMS (0.9 Hz, 100% of motor threshold, 20 min) applied to the left temporoparietal cortex was used for 10 days in the treatment of medication-resistant auditory hallucinations in schizophrenia (n = 12). The effect of rTMS on the low-resolution brain electromagnetic tomography (LORETA) and brain metabolism (18FDG PET) was measured before and after 2 weeks of treatment. Results: We found a significant improvement in the total and positive symptoms (PANSS), and on the hallucination scales (HCS, AHRS). The rTMS decreased the brain metabolism in the left superior temporal gyrus and in interconnected regions, and effected increases in the contralateral cortex and in the frontal lobes. We detected a decrease in current densities (LORETA) for the beta-1 and beta-3 bands in the left temporal lobe whereas an increase was found for beta-2 band contralaterally. Conclusion: Our findings implicate that the effect is connected with decreased metabolism in the cortex underlying the rTMS site, while facilitation of metabolism is propagated by transcallosal and intrahemispheric connections. The LORETA indicates that the neuroplastic changes affect the functional laterality and provide the substrate for a metabolic effect.

Guidelines for the Recording and Evaluation of Pharmaco-EEG Data in Man: The International Pharmaco-EEG Society (IPEG)

The International Pharmaco-EEG Society (IPEG) presents updated guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-EEG data in man. Since the publication of the first pharmaco-EEG guidelines in 1982, technical and data processing methods have advanced steadily, thus enhancing data quality and expanding the palette of tools available to investigate the action of drugs on the central nervous system (CNS), determine the pharmacokinetic and pharmacodynamic properties of novel therapeutics and evaluate the CNS penetration or toxicity of compounds. However, a review of the literature reveals inconsistent operating procedures from one study to another. While this fact does not invalidate results per se, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. Moreover, this shortcoming hampers reliable comparisons between outcomes of studies from different laboratories and hence also prevents pooling of data which is a requirement for sufficiently powering the validation of novel analytical algorithms and EEG-based biomarkers. The present updated guidelines reflect the consensus of a global panel of EEG experts and are intended to assist investigators using pharmaco-EEG in clinical research, by providing clear and concise recommendations and thereby enabling standardisation of methodology and facilitating comparability of data across laboratories.

Objective assessment of the degree of dementia by means of EEG.

The aim of the study was to elaborate a method to estimate the degree of cognitive impairment in Alzheimer’s disease from the EEG quantitative indicators. We examined 38 unmedicated patients with a diagnosis of Alzheimer’s disease, with various stages (mild, moderate, and severe) of dementia. The EEG recordings were evaluated both visually and by means of computer analysis. The EEG spectra and coherences in 6 frequency bands were calculated in 16 EEG derivations. Among various EEG indicators, a decrease in the alpha coherence and an increase in the delta coherence was found to be most significantly correlated to the degree of dementia. Combining 6 variables from the spectrum and coherence analysis by means of the multiple regression model, a high correlation (r = 0.87) between a set of EEG variables and the Mini-Mental State Examination score could be obtained. The results suggest that the EEG can supplement the clinical examination by providing an independent assessment of the degree of dementia. The results also suggest that the EEG coherences are of particular interest in dementia, being an indicator of the signal transfer between various parts of the brain cortex.

Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: voxel-based-morphometry (VBM) study.

Abstract Objectives. To address the role of latent T. gondii infection in schizophrenia we studied the influence of latent toxoplasmosis on brain morphology. Methods. An optimized voxel-based morphometry of magnetic resonance imaging was analyzed by analysis of variance with diagnosis and seropositivity as factors in 44 schizophrenic patients (12 T. gondii positive) and 56 controls (13 T. gondii positive). Results. Grey matter (GM) volume was reduced in schizophrenia patients compared with controls in the cortical regions, hippocampus and in the caudate. In the schizophrenia sample we found a significant reduction of GM volume in T. gondii positive comparing with T. gondii-negative patients bilaterally in the caudate, median cingulate, thalamus and occipital cortex and in the left cerebellar hemispheres. T. gondii-positive and -negative controls did not differ in any cluster. Among participants seropositive to T. gondii the reduction of GM in the schizophrenia subjects was located in the same regions when comparing the entire sample (11,660 over-threshold voxels (P ≤ 0.05, FWR corrected). The differences between T. gondii-negative patients and controls consisted only of 289 voxels in temporal regions. Conclusions. Our study is the first to document that latent toxoplasmosis reduces GM in schizophrenia but not in controls.

The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments

UNLABELLED The aim of the study was to examine whether the reduction of theta prefrontal quantitative EEG (QEEG) cordance after one week of bupropion administration is a predictor of response to a 4-week treatment in patients that had failed to respond to previous antidepressant treatments. METHOD EEG data of 18 inpatients were monitored at baseline and after one week. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz). Response to treatment was defined as a >/=50% reduction of MADRS score. RESULTS Nine of the eleven responders and one of the seven non-responders showed decreased prefrontal cordance value after the first week of treatment (p=0.01). Positive and negative predictive values of cordance reduction for the prediction of response to the treatment were 0.9 and 0.75, respectively. CONCLUSION Similar to other antidepressants, the reduction of prefrontal QEEG cordance might be helpful in the prediction of the acute outcome of bupropion treatment.

Low frequency (1-Hz), right prefrontal repetitive transcranial magnetic stimulation (rTMS) compared with venlafaxine ER in the treatment of resistant depression: a double-blind, single-centre, randomized study.

BACKGROUND Previous studies have shown effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. This double-blind study compared efficacy of l Hz rTMS over the right prefrontal dorsolateral cortex with venlafaxine ER in the treatment of resistant depression. METHODS A total of 60 inpatients with depressive disorder (DSM-IV criteria), who previously did not respond to at least one antidepressant treatment, were randomly assigned to 1 Hz rTMS with placebo and venlafaxine ER with sham rTMS for 4 weeks. The primary outcome measure was score change in the Montgomery-Asberg Depression Rating Scale (MADRS). We also used Clinical Global Impression (CGI) and Beck Depressive. Inventory-Short Form (BDI-SF). The response was defined as a >or=50% reduction of MADRS score. RESULTS There were no significant differences between treatment groups in MADRS (p=0.38), BDI-SF (p=0.56) and CGI (p=0.17) scores from baseline to endpoint. Response rates for rTMS (33%) and venlafaxine (39%) as well as remission (MADRS score<or=10 points) rates (19% vs. 23%) and drop-out rate did not differ between treatment groups. There were significant reductions of MADRS, CGI and BDI-SF scores in both groups. LIMITATIONS Small sample size. No placebo arm was included for ethical reasons, because both treatments have previously been reported to be more effective than placebo. Relatively short duration of antidepressant treatment. CONCLUSION The findings of this study suggest that, at least in the acute treatment, the right sided rTMS produces clinically relevant reduction of depressive symptomatology in patients with resistant depression comparable to venlafaxine ER. Larger sample sizes are required to confirm these results.

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect

BACKGROUND Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. METHOD In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. RESULTS Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. CONCLUSIONS Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

Standardized low-resolution brain electromagnetic tomography (sLORETA) in the prediction of response to cholinesterase inhibitors in patients with Alzheimer's disease

Materials and methods Resting EEG was recorded in 20 mild to moderate AD patients (mean age= 75.04 years; 13 women and 7 men; MMSE 15-24) before and after 6 months and 2 years on ChEI (donepezil, rivastigmine, galantamine) treatment. Based on changes of MMSE scores after 2 years follow-up, 11 patients were classified as Non-responders (decrease of MMSE > 2) and 9 patients as Responders (decrease of MMSE < 2). The localization of the differences in activity between two groups (at baseline) and within groups (baseline vs. 6 months) was assessed by voxel-by-voxel ttests of the sLORETA images of the log-transformed computed current density power in seven frequency bands.

Discontinuation of hypnotics during cognitive behavioural therapy for insomnia

BackgroundIn practical sleep medicine, therapists face the question of whether or not to discontinue the ongoing use of hypnotics in patients, as well as the possible effects of discontinuation. The aim of this study was to evaluate the effects of discontinuing third-generation hypnotics on the results of cognitive-behavioural therapy (CBT) for primary insomnia in patients after long-term abuse.MethodsTwenty-eight outpatients were treated by CBT for 8 weeks. The treatment outcome was estimated by means of differences among subjective clinical scales and polysomnography variables assessed before and after the treatment period. The therapeutic effect in a subgroup of 15 patients who had previously received hypnotics and were successively withdrawn during weeks 2–6 was compared to the effect achieved in patients who had not used hypnotics before CBT.ResultsThere were no significant differences in baseline subjective and objective sleep characteristics between the hypnotic abusers and non-abusers. According to clinical scales and most polysomnographic measures, CBT was highly effective in both groups of subjects; it produced the greatest changes in total sleep time, REM sleep and sleep efficiency. Unexpectedly, discontinuation of hypnotics, as a factor in the analysis, was followed by an additional improvement of sleep efficiency and wake after sleep onset parameters.ConclusionOur study confirmed the efficacy of CBT in both hypnotic-abusing and non-abusing patients with chronic insomnia. The results of this study suggest that tapered withdrawal of third-generation hypnotics during CBT therapy for chronic insomnia could be associated with improvement rather than worsening of sleep continuity.

LORETA functional imaging in antipsychotic-naive and olanzapine-, clozapine- and risperidone-treated patients with schizophrenia.

The aim of our study was to detect changes in the distribution of electrical brain activity in schizophrenic patients who were antipsychotic naive and those who received treatment with clozapine, olanzapine or risperidone. We included 41 subjects with schizophrenia (antipsychotic naive = 11; clozapine = 8; olanzapine = 10; risperidone = 12) and 20 healthy controls. Low-resolution brain electromagnetic tomography was computed from 19-channel electroencephalography for the frequency bands delta, theta, alpha-1, alpha-2, beta-1, beta-2 and beta-3. We compared antipsychotic-naive subjects with healthy controls and medicated patients. (1) Comparing antipsychotic-naive subjects and controls we found a general increase in the slow delta and theta frequencies over the fronto-temporo-occipital cortex, particularly in the temporolimbic structures, an increase in alpha-1 and alpha-2 in the temporal cortex and an increase in beta-1 and beta-2 in the temporo-occipital and posterior limbic structures. (2) Comparing patients who received clozapine and those who were antipsychotic naive, we found an increase in delta and theta frequencies in the anterior cingulate and medial frontal cortex, and a decrease in alpha-1 and beta-2 in the occipital structures. (3) Comparing patients taking olanzapine with those who were antipsychotic naive, there was an increase in theta frequencies in the anterior cingulum, a decrease in alpha-1, beta-2 and beta-3 in the occipital cortex and posterior limbic structures, and a decrease in beta-3 in the frontotemporal cortex and anterior cingulum. (4) In patients taking risperidone, we found no significant changes from those who were antipsychotic naive. Our results in antipsychotic-naive patients are in agreement with existing functional findings. Changes in those taking clozapine and olanzapine versus those who were antipsychotic naive suggest a compensatory mechanism in the neurobiological substrate for schizophrenia. The lack of difference in risperidone patients versus antipsychotic-naive subjects may relate to risperidone’s different pharmacodynamic mechanism.