Ultra-high-frequency left prefrontal transcranial magnetic stimulation as augmentation in severely ill patients with depression: a naturalistic sham-controlled, double-blind, randomized trial

Background and Aim: Repetitive transcranial magnetic stimulation (rTMS) is supposed to be not as effective in severe depression as it is in medium depression. We evaluated the treatment response to an ultra-high-frequency (UHF; 30 Hz) approach, which was used to maximize the rTMS efficacy in severely ill patients. Methods: 43 severely depressed patients were included in the randomized, double-blind study and received either rTMS with 30 Hz over the left dorsolateral prefrontal cortex or sham condition for 3 weeks as an add-on therapy to stable antidepressant medication. Hamilton Depression Rating Scale (HDRS) and cognitive performance were evaluated before and after the intervention. Results: In the active UHF group, the HRDS score was reduced by about 7.2, whereas the sham condition showed a smaller reduction of the HDRS score with 3.9. However, lithium as a covariant was responsible for the outcome difference, not the group of stimulation. No adverse events were reported. Comparing the differences of both groups in the pre- and post-study performance in a trail-making test, a group effect for the UHF group that was not influenced by the lithium intake was observed. Conclusion: A 30-Hz left prefrontal rTMS in severely depressed patients was safe and no adverse events occurred. Due to a strong effect of lithium as a covariate, we could not demonstrate favorable antidepressant effects of the UHF stimulation compared to sham. However, we found an improvement of processing speed performance in the UHF group, which covaried with improvement of psychomotor retardation. Copyright (C) 2012 S. Karger AG, Base

Long-term course of brain-derived neurotrophic factor serum levels in a patient treated with deep brain stimulation of the lateral habenula

Introduction: According to the neurotrophin hypothesis, a brain-derived neurotrophic factor (BDNF) decrease has been postulated as a pivotal pathomechanism in affective disorder, and the treatment-associated increase in peripheral BDNF has been linked to therapeutic efficacy of antidepressant drugs and electroconvulsive therapy. However, in deep brain stimulation (DBS), a still experimental antidepressant treatment approach, this issue has not yet been investigated. Methods: We examine the long-term course of serum BDNF levels in a 64-year-old woman who is being treated with DBS of the lateral habenula for severe major depressive disorder. Results: Our main findings are a significant increase in BDNF serum levels following DBS of the lateral habenula and an inverse U-shaped correlation of depression scores and BDNF levels. Discussion: The data indicate that DBS, like other effective antidepressant treatments, may contribute to an increase in peripheral BDNF levels, which are thought to reflect central nervous DBS-induced neuroplastic changes. Moreover, our observations underscore the complex nature of disease-associated BDNF alterations. Their identification as either state or trait marker remains controversial and requires larger-scale longitudinal studies. Copyright (C) 2012 S. Karger AG, Base

Electroconvulsive therapy does not alter the synaptic protein neurogranin in the cerebrospinal fluid of patients with major depression

Neurogranin (Ng) is a dendritic protein associated with synaptic plasticity, proposed to be a novel biomarker to measure synaptic dysfunction and degeneration in Alzheimer’s disease. Since electroconvulsive therapy (ECT) has been suggested to facilitate neurogenesis and neural plasticity, we tested whether ECT could modify CSF Ng concentrations measured before and after a course of ECT in 12 patients with major depression. CSF Ng concentrations did not change, but baseline levels were positively correlated with the therapeutic response

CSF Metabolic and Proteomic Profiles in Patients Prodromal for Psychosis

BACKGROUND: The initial prodromal state of psychosis (IPS) is defined as an early disease stage prior to the onset of overt psychosis characterized by sub-threshold or more unspecific psychiatric symptoms. Little is known regarding the biochemical changes during this period. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the metabolic/proteomic profiles of cerebrospinal fluid (CSF) of first-onset drug naïve paranoid schizophrenia patients (n = 54) and individuals presenting with initial prodromal symptoms (n = 24), alongside healthy volunteers (n = 70) using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy and surface enhanced laser desorption ionization (SELDI) mass spectrometry, respectively. Partial least square discriminant analysis (PLS-DA) showed that 36%/29% of IPS patients displayed proteomic/metabolic profiles characteristic of first-onset, drug naïve schizophrenia, i.e., changes in levels of glucose and lactate as well as changes in a VGF-derived peptide (VGF23-62) and transthyretin protein concentrations. However, only 29% (n = 7) of the investigated IPS patients (who to date have been followed up for up to three years) have so far received a diagnosis of schizophrenia. The presence of biochemical alterations in the IPS group did not correlate with the risk to develop schizophrenia. CONCLUSIONS/SIGNIFICANCE: Our results imply that schizophrenia-related biochemical disease processes can be traced in CSF of prodromal patients. However, the biochemical disturbances identified in IPS patients, at least when measured at a single time point, may not be sufficient to predict clinical outcome

Rudimentary G-Quadruplex-Based Telomere Capping In Saccharomyces Cerevisiae

Telomere capping conceals chromosome ends from exonucleases and checkpoints, but the full range of capping mechanisms is not well defined. Telomeres have the potential to form G-quadruplex (G4) DNA, although evidence for telomere G4 DNA function in vivo is limited. In budding yeast, capping requires the Cdc13 protein and is lost at nonpermissive temperatures in cdc13-1 mutants. Here, we use several independent G4 DNA-stabilizing treatments to suppress cdc13-1 capping defects. These include overexpression of three different G4 DNA binding proteins, loss of the G4 DNA unwinding helicase Sgs1, or treatment with small molecule G4 DNA ligands. In vitro, we show that protein-bound G4 DNA at a 3\u27 overhang inhibits 5\u27-\u3e 3\u27 resection of a paired strand by exonuclease I. These findings demonstrate that, at least in the absence of full natural capping, G4 DNA can play a positive role at telomeres in vivo

Source-Reconstruction of Event-Related Fields Reveals Hyperfunction and Hypofunction of Cortical Circuits in Antipsychotic-Naive, First-Episode Schizophrenia Patients during Mooney Face Processing

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n � 14) and healthy control participants (n � 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A�). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission

Differential effect of interferon-alpha treatment on AEA and 2-AG levels.

The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), following immunotherapy with IFN-α and in IFN-α -induced depression, have not been examined yet. In this study, we investigated whether circulating AEA and 2-AG were modified by treatment with IFN-α and whether they were involved in the development of IFN-α-induced depression. We also explored whether circulating eCBs were associated with peripheral cytokines during and after IFN-α treatment. We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery electrochemiluminescence V-PLEX assay, in 70 patients with HCV infection and 41 healthy subjects. We assessed HCV patients at baseline, IFN-α-treatment weeks (TW) 4 and 24, end of treatment (END) and at six months follow-up (FU). We assessed depression using M.I.N.I. International Neuropsychiatric Interview. We found a different pattern of change in peripheral AEA and 2-AG during and after IFN-α treatment. Whilst 2-AG increased earlier in immunotherapy (TW4), remained elevated throughout treatment, and reduced at six months follow-up (FU), AEA increased later in treatment (TW24) and remained elevated six months post-treatment. We also found that baseline levels of AEA were lower in HCV patients compared with healthy controls, whereas there were no differences in 2-AG levels. Interestingly, AEA, but not 2-AG, was significantly, negatively correlated with interleukin (IL)-2 and IL-17a at six months follow-up. We did not find any difference in both eCBs between patients with and without IFN-α-induced depression, at any time point. Our findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation. Lack of association between peripheral eCBs and IFN-α-induced depression suggests that different biological mechanisms may underpin inflammation-induced depression compared with classic "psychiatric" depression, or that any changes in the eCB system in depression may not be captured by peripheral AEA and 2-AG

Validation of a Blood-Based Laboratory Test to Aid in the Confirmation of a Diagnosis of Schizophrenia

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls

Quantitative analysis of the binding affinity of poly(ADP-ribose) to specific binding proteins as a function of chain length

Poly(ADP-ribose) (PAR) is synthesized by poly(ADP-ribose) polymerases in response to genotoxic stress and interacts non-covalently with DNA damage checkpoint and repair proteins. Here, we present a variety of techniques to analyze this interaction in terms of selectivity and affinity. In vitro synthesized PAR was end-labeled using a carbonyl-reactive biotin analog. Binding of HPLC-fractionated PAR chains to the tumor suppressor protein p53 and to the nucleotide excision repair protein XPA was assessed using a novel electrophoretic mobility shift assay (EMSA). Long ADP-ribose chains (55-mer) promoted the formation of three specific complexes with p53. Short PAR chains (16-mer) were also able to bind p53, yet forming only one defined complex. In contrast, XPA did not interact with short polymer, but produced a single complex with long PAR chains (55-mer). In addition, we performed surface plasmon resonance with immobilized PAR chains, which allowed establishing binding constants and confirmed the results obtained by EMSA. Taken together, we developed several new protocols permitting the quantitative characterization of PAR–protein binding. Furthermore, we demonstrated that the affinity of the non-covalent PAR interactions with specific binding proteins (XPA, p53) can be very high (nanomolar range) and depends both on the PAR chain length and on the binding protein