Is 1 Hz rTMS Always Inhibitory in Healthy Individuals?

1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) is considered to have an inhibitory effect in healthy people because it suppresses the excitability of the motor or visual cortex that is expressed as an increase in the motor or the phosphene threshold (PT), respectively. However, the underlying mechanisms and the brain structures involved in the action of rTMS are still unknown. In this study we used two sessions of simultaneous TMS-functional magnetic resonance imaging (fMRI), one before and one after, 15 minutes of 1Hz rTMS to map changes in brain function associated with the reduction in cortical excitability of the primary visual cortex induced by 1 Hz rTMS, when TMS was applied on the occipital area of healthy volunteers. Two groups were evaluated, one group composed of people that can see phosphenes, and another of those lacking this perception. The inhibitory effect, induced by the 1 Hz rTMS, was observed through the increase of the PT, in the first group, but did not lead to a global reduction in brain activation, instead, showed change in the activation pattern before and after rTMS. Conversely, for the second group, changes in brain activation were observed just in few brain areas, suggesting that the effect of 1 Hz rTMS might not be inhibitory for everyone and that the concept of inhibitory/excitatory effect of rTMS may need to be revised.

[Dementia and depression determine care dependency in Parkinson's disease: analysis of 1,449 outpatients receiving nursing care in Germany]. / Demenz und Depression determinieren Pflegebedürftigkeit bei M. Parkinson : Untersuchung an 1449 Patienten im ambulanten Versorgungssektor in Deutschland.

BACKGROUND: Parkinson's disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. PATIENTS AND METHODS: A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8-4.3), dementia (OR=2.7; 95% CI 1.8-4.1) or both (OR=3.9; 95% CI 2.5-60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3-5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). CONCLUSION: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

[The German Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD): more than Parkinson]. / Die "German study on the epidemiology of Parkinson's disease with dementia" (GEPAD): mehr als nur Parkinson.

UNLABELLED: It is unknown, how frequently Parkinson's disease (PD) is complicated by dementia, depression and other neuropsychiatric conditions. An epidemiologic characterisation of the situation in specialised neurologic settings is lacking. The Geman Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD) isa national representative epidemiological study of n=1449 PD patients in n=315 office-based neurological settings, designed to estimate the prevalence of dementia, depression and other neuropsychiatric conditions in patients with PD of all stages by using standardized clinical assessments. RESULTS: 28.6% met DSM-IV criteria for dementia. 33.6% met criteria for depression and 61% additionally had other clinically significant psychopathological syndromes. Only 29.4% had no neuropsychiatric conditions. GEPAD reveals for the first time comprehensively that the neuropsychiatric burden of PD patients in all stages and even early stages is considerable, posing challenging questions for research and clinical management.

Simultaneous TMS-fMRI of the Visual Cortex Reveals Functional Network, Even in Absence of Phosphene Sensation.

Phosphene sensation is commonly used to measure cortical excitability during transcranial magnetic stimulation (TMS) of the occipital cortex. However, some individuals lack this perception, and the reason for it is still unknown. In this work, we used functional magnetic resonance imaging (fMRI) to detect brain activation during local TMS of the occipital cortex in twelve healthy subjects. We found that TMS modulated brain activity in areas connected to the stimulation site, even in people unable to see phosphene. However, we observed a trend for a lower blood-oxygenation-level dependent (BOLD) signal, and smaller brain-activation clusters near the stimulated site than in the interconnected brain areas, suggesting that TMS pulse is more effective downstream than at its application site. Furthermore, we noted prominent differences in brain activation/deactivation patterns between subjects who perceived phosphene and those who did not, implying a functional distinction in their neuronal networks that might explain the origin of differences in phosphene generation.

Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression.

BACKGROUND: It has been widely accepted that glial pathology and disturbed synaptic transmission contribute to the neurobiology of depression. Apart from monoaminergic alterations, an influence of glutamatergic signal transduction has been reported. Therefore, gene expression of glutamate transporters that strictly control synaptic glutamate concentrations have to be assessed in animal models of stress and depression. METHODS: We performed in situ-hybridizations in learned helplessness rats, a well established animal model of depression, to assess vGluT1 and EAAT1-4. Sprague-Dawley rats of two inbred lines were tested for helpless behavior and grouped into three cohorts according to the number of failures to stop foot shock currents by lever pressing. RESULTS: Helpless animals showed a significantly suppressed expression of the glial glutamate transporter EAAT2 (rodent nomenclature GLT1) in hippocampus and cerebral cortex compared to littermates with low failure rate and not helpless animals. This finding was validated on protein level using immunohistochemistry. Additionally, expression levels of EAAT4 and the vesicular transporter vGluT1 were reduced in helpless animals. In contrast, the transcript levels of EAAT1 (GLAST) and EAAT3 (EAAC1) were not significantly altered. CONCLUSIONS: These results strongly suggest reduced astroglial glutamate uptake and implicate increased glutamate levels in learned helplessness. The findings are in concert with antidepressant effects of NMDA-receptor antagonists and the hypotheses that impaired astroglial functions contribute to the pathogenesis of affective disorders.

Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing.

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Reduced expression of GABA transporter GAT3 in helpless rats, an animal model of depression.

Mood disorders have been linked to glial and synaptic pathology such as disturbed neurotransmission of gamma-aminobutyric acid (GABA). We evaluated the expression of GABAergic marker genes in rats with helpless behaviour, an animal model of depression. Male Sprague-Dawley rats from inbred lines were tested for helpless behaviour and grouped according to failures in terminating foot shock currents. Expression levels of GABAergic marker genes were assessed using semiquantitative in situ-hybridization. Animals with congenital helpless behaviour (cH) were unable to escape current exposure in contrast to cH-animals derived from the same litters with low failure rates and to non-helpless animals (cNH). We found a significant downregulation of the GABA transporter GAT3 in cLH rats. GAT1 showed small changes, glutamic acid decarboxylase (GAD67) and the vesicular GABA transporter were not significantly altered. Reduced GABA transporter expression is well in concert with the behavioural phenotypes of knockout animals and strengthens the hypothesis of impaired glial functions in depression.

Dehydration enthalpy of alkali-cations-exchanged montmorillonite from thermogravimetric analysis.

Dehydration of a series of homoionic alkali-exchanged montmorillonites is studied at different treatment temperatures by means of thermogravimetric analysis. More specifically, we investigate the last stages of dehydration when the number of adsorbed water molecules corresponds, at maximum, to a monolayer. Weight losses are measured at several constant temperatures as a function of time. Application of Van't Hoff's law yields the dehydration enthalpy. Trends and data similar to those reported from other experimental conditions are found. Comparison with X-ray data and with the dissociation enthalpy of alkali cation/water complexes shows that dehydration of weakly hydrated homoionic alkali montmorillonites results from the competition between opposite energy contributions due to (i) the cation solvation, (ii) the hydration of the silicate interlayer surface, and (iii) the structural swelling. So, depending on the balance between these various energy contributions, different behaviors are observed according to the nature of the alkali cations.

Metabolomics of neural progenitor cells: a novel approach to biomarker discovery.

Finding biomarkers of human neurological diseases is one of the most pressing goals of modern medicine. Most neurological disorders are recognized too late because of the lack of biomarkers that can identify early pathological processes in the living brain. Late diagnosis leads to late therapy and poor prognosis. Therefore, during the past decade, a major endeavor of clinical investigations in neurology has been the search for diagnostic and prognostic biomarkers of brain disease. Recently, a new field of metabolomics has emerged, aiming to investigate metabolites within the cell/tissue/ organism as possible biomarkers. Similarly to other "omics" fields, metabolomics offers substantial information about the status of the organism at a given time point. However, metabolomics also provides functional insight into the biochemical status of a tissue, which results from the environmental effects on its genome background. Recently, we have adopted metabolomics techniques to develop an approach that combines both in vitro analysis of cellular samples and in vivo analysis of the mammalian brain. Using proton magnetic resonance spectroscopy, we have discovered a metabolic biomarker of neural stem/progenitor cells (NPCs) that allows the analysis of these cells in the live human brain. We have developed signal-processing algorithms that can detect metabolites present at very low concentration in the live human brain and can indicate possible pathways impaired in specific diseases. Herein, we present our strategy for both cellular and systems metabolomics, based on an integrative processing of the spectroscopy data that uses analytical tools from both metabolomic and spectroscopy fields. As an example of biomarker discovery using our approach, we present new data and discuss our previous findings on the NPC biomarker. Our studies link systems and cellular neuroscience through the functions of specific metabolites. Therefore, they provide a functional insight into the brain, which might eventually lead to discoveries of clinically useful biomarkers of the disease.

Behavioural alterations in rats following neonatal hypoxia and effects of clozapine: implications for schizophrenia.

INTRODUCTION: As a consequence of obstetric complications hypoxia has been discussed as a possible factor in the pathophysiology of schizophrenia. The present study investigated the effects of weak chronic neonatal hypoxia in rats on different behavioural animal models of schizophrenia. METHODS: (1) After neonatal hypoxia, half of the pups were fostered by normally treated nurse animals to control for possible maternal effects. (2) The animals were tested on postnatal days (PD) 36, 86, 120 and 150 by applying three different behavioural tests: prepulse inhibition (PPI), social interaction and recognition, and motor activity in an open field. (3) Before the PD 150 test, half of the animals had been chronically treated with the antipsychotic drug clozapine (45 mg/kg/day). RESULTS: Rats exposed to hypoxia as neonates exhibited a deficit in locomotor activity on PD 86, 120, and 150, as well as a PPI deficit on PD 120 and 150 but not before. Chronic treatment with clozapine reverses the hypoxia induced PPI deficit, but not the decreased locomotor activity. In a second experiment, clozapine was chronically administered before PD 120 and blocked the development of the PPI deficit in the animals exposed to hypoxia. DISCUSSION: The time course of the hypoxia-induced PPI deficit and reversibility by clozapine supports the validity of our animal model and the hypothesis that hypoxia as an obstetric complication is an important factor in the pathophysiology of schizophrenia.

Hydration of a Na(+)-montmorillonite studied by thermally stimulated depolarization current.

Thermally stimulated depolarization current (TSDC) technique is a powerful tool for probing dipole re-orientational motions in condensed matter. In the case of cation-exchangeable aluminosilicates, it allows the assessment of the potential barrier related to the hopping mechanism of cations and, consequently, the measurement of its evolution when molecules, i.e. water, are adsorbed and interact with the cations embedded in the solid framework. Then, using suitable models based on thermodynamics, the analysis of TSDC signals obtained at various hydration states provides insights about the surface properties of the studied solid and the mechanism of adsorption at the cationic site. In this work, TSDC is used to study the first stage, i.e. when the number of adsorbed molecules is below the occurrence of the water monolayer, of water adsorption in a Na(+)-montmorillonite from Mostaganem (Algeria). It is shown that the hydration process follows two stages. Using the "chemical force" concept it can then be concluded that when the number of adsorbed water molecules per cation is lower than 2, cation-water interaction dominates the energetics of adsorption, whereas at higher water loading the water "chemical force" is also involved into water-water and/or water-clay framework interactions. The number of water molecules for the monohydrated state is found to be about 7.

Altered NMDA receptor expression and behavior following postnatal hypoxia: potential relevance to schizophrenia.

The present study investigated the effects of chronic, repeated hypoxia during a postnatal vulnerable period. Acoustic startle response in adult rats was measured along with NMDA receptor binding and mRNA expression of subunits at postnatal days (PND) 11 and 120. Rats at PND 120 exhibited a deficit in prepulse inhibition of acoustic startle response. In PND 11 rats, chronic hypoxia decreased NMDA receptor binding and increased transcript expression of NR1 subunit in frontal and temporal regions, nucleus accumbens and hippocampus, while NR2A subunit expression was downregulated in hippocampal subregions. At PND 120, gene expression of NR1 was still increased in hippocampal, frontal and temporal subregions as well as nucleus accumbens. A prepulse inhibition deficit points to schizophrenia-like behavior in adult (PND 120) rats. Compensatory upregulation of NR1 expression may occur due to NMDA receptor hypofunction. We discuss this animal model to further analyze effects of hypoxia as a factor of obstetric complications in the pathophysiology of schizophrenia.

Use of dielectric relaxation for measurements of surface energy variations during adsorption of water on mordenite.

This paper tries to assess simply and quantitatively the link between classical adsorption theories and dielectric spectroscopy, in order to demonstrate that dielectric spectroscopy can be used as a tool of determination of surface energy variations due to movements of charge carriers at the surface of solids. A simple theory is developed to analyze hops of cations at the surface of mordenite, which are detected by complex impedance spectroscopy during adsorption of water. An energy of extraction of the cation can be determined from measurements and its dependence on the quantity of water molecules adsorbed is shown and qualitatively and quantitatively explained, using relationships developed in order to interpret adsorption phenomena generally. The agreement with other determinations of the adsorption energies and solid surface energy is correct.

ECT anesthesia: the lighter the better?

BACKGROUND: Electroconvulsive therapy (ECT) is a most effective treatment for patients with major affective disorders. The influence of anesthetic drugs on seizure "adequacy" or on treatment success has not been systematically investigated. METHODS: A bispectral EEG index score (BIS) was used to identify the depth of anesthesia during ECT. Our study included 22 major depressive episode (MDE) patients expanding to 219 ECTs (05/05-01/06) with no limitations of concurrent medication. RESULTS: Fourteen out of the 22 patients showed full remission. Individual number of ECT sessions needed to reach full remission correlated negatively with mean pre-ECT BIS values (p=0.001). Additionally, using a repeated measurement regression analysis significant correlations were found for pre-ECT BIS versus motor response time, seizure concordance, ictal coherence and peak heart rate. CONCLUSION: The results of our study suggest BIS-levels as a predictor of faster ECT response. Controlling BIS-levels before stimulation may have an additional effect on treatment success.

Cation migration upon adsorption of methanol in NaY and NaX faujasite systems: a molecular dynamics approach.

Molecular dynamics simulations have been carried out to address the question of cation migration upon adsorption of methanol in NaY and NaX faujasite systems as a function of the loading. For NaY, it has been shown that, at low and intermediate loadings, SII cations can migrate toward the center of the supercage due to strong interactions with the adsorbates, followed by a hopping of SI' from the sodalite cage into the supercage to fill the vacant SII site. A SI' cation can also migrate across the double six ring and takes a SI' vacant position. SI cations mainly remain trapped in their initial sites whatever the loading. At high loading, only limited motions are observed for SII cations due to steric effects induced by the presence of adsorbates within the supercage. For NaX, the SIII' cations which occupy the most accessible adsorption sites are significantly moving upon coordination to the methanol molecules; the extent of this mobility exhibits a maximum for 48 methanol molecules per unit cell before decreasing at higher loadings due to steric hindrance. In addition, the SI' and SII cations remain almost trapped in their initial sites whatever the loading. Indeed, the most probable migration mechanism involves SIII' cation displacements into nearby SIII' sites.

[Treating depressive disorders with continuation electroconvulsive therapy]. / Erhaltungselektrokrampftherapie bei depressiven Störungen.

Nowadays, electroconvulsive therapy (ECT) is undergoing a renaissance in psychiatry: it is now considered a first-line therapy for treating psychotic depression or other disorders with severe depressive symptoms. Surprisingly, ECT is most commonly not used as continuation therapy after acute remission. With rare exceptions, antidepressive medication is chosen for this purpose. The use of continuation ECT (cECT) and subsequent maintenance ECT (mECT) is not or just marginally mentioned in practice guidelines. In this article, we suggest guidelines for cECT, taking therapy recommendations and recent studies into account. Particularly, indication, management, comedication and comorbidity, side effects, and costs are examined. Today, cECT is underindicated as a result of assumed problems, fears, and stigmas. We would therefore recommend broader use of this proven treatment tool for keeping major depression in remission.

Reduced sensitivity to sucrose in rats bred for helplessness: a study using the matching law.

Anhedonia is a core symptom of depression. As it cannot be directly assessed in rodents, anhedonia is usually inferred from a reduced consumption of, or preference for, a reinforcer. In the present study we tried to improve the measurement of anhedonia by performing a detailed preference analysis based on the generalized matching law and tested its sensitivity in rats congenitally prone (cLH) or resistant (cNLH) to learned helplessness. According to the current interpretation of learned helplessness as a model for depression, a reduction in the rewarding properties of sucrose in cLH rats was hypothesized. Our results revealed that the 'preference allocation' index provided by this test, but not the traditional measures of sucrose consumption or preference over water, was significantly lower in cLH rats, and was correlated with the helpless behaviour as measured in an escape procedure. Therefore, it is clear that more subtle preference measures provided by the analysis of choice using the matching law principles are more sensitive and discriminative than those based on consumption of, or preference for, a single concentration of sucrose over water. Moreover, our data are in agreement with the proposed relationship between helplessness and sucrose preference, and support the usefulness of the cLH and cNLH rats as a model of depression.

Simple model for ac ionic conduction in solids.

We present a model for the ac conduction in ionically conducting solids that takes into account, in a simple way, the interaction between carriers. The Coulomb force forms an "ionic atmosphere" that exerts a restoring force on a central ion, whose motion corresponds to an overdamped oscillator. We consider the effect of the relaxation of the ionic atmosphere by introducing an additional equation for the displacement of the potential toward the particle position. The general behavior of the ac conductivity can be understood in terms of two types of motions: motion of the bound ion at high frequencies determined by microscopic friction, and a much slower motion coupled to the surrounding carriers relaxation at low frequencies.