Deep brain stimulation in schizophrenia

Deep brain stimulation (DBS) has successfully advanced treatment options of putative therapy-resistant neuropsychiatric diseases. Building on this strong foundation more and more mental disorders in the stadium of therapy-resistance are considered as possible indications for DBS. Especially schizophrenia with its associated severe and difficult to treat symptoms is gaining attention. This attention demands critical questions regarding the assumed mechanisms of DBS and its possible influence on the supposed pathophysiology of schizophrenia. Here we synoptically compare current approaches and theories of DBS and discuss the feasibility of DBS in schizophrenia as well as the transferability from other psychiatric disorders successfully treated with DBS. For this we consider recent advances in animal models of schizophrenic symptoms, results regarding the influence of DBS on dopaminergic transmission as well as data concerning neural oscillation and synchronization. In conclusion the use of DBS for some symptoms of schizophrenia seems to be a promising approach, but the lack of a comprehensive theory of the mechanisms of DBS as well as its impact on schizophrenia might void the use of DBS in schizophrenia at this point

Why dried blood spots are an ideal tool for CYP1A2 phenotyping

Background and Objective: Dried blood spot (DBS) sampling has gained wide interest in bioanalysis during the last decade and has already been successfully applied in pharmacokinetic and phenotyping studies. However, all of the available phenotyping studies used small datasets and did not include a systematic evaluation of DBS-specific parameters. The latter is important since several of these factors still challenge the breakthrough of DBS in routine practice. In this study, caffeine and paraxanthine are determined in capillary DBS, venous DBS, whole blood and plasma for cytochrome P450 (CYP) 1A2 phenotyping. The aim of this study was to explore the usefulness of DBS as a tool for CYP1A2 phenotyping. Methods: A CYP1A2 phenotyping study was conducted in 73 healthy volunteers who received a 150 mg oral dose of caffeine. Six hours post-administration, caffeine and paraxanthine concentrations and paraxanthine:caffeine molar concentration ratios, i.e., the actual CYP1A2 phenotyping indices, were determined in capillary DBS (obtained by non-volumetric application, direct from the fingertip), venous DBS, whole blood, and plasma. Furthermore, the impact of DBS-specific parameters, including hematocrit, volume spotted, and punch location, was evaluated. Results: Concentrations of caffeine and paraxanthine in capillary DBS were, respectively, on average 12.7 and 13.8 % lower than those in venous DBS and 31.5 and 33.1 % lower than those in plasma. While these differences were statistically significant (p = 0.053). This ratio also alleviated the impact of hematocrit and volume spotted. Conclusions: Using the largest DBS-based phenotyping study to date, we have demonstrated that CYP1A2 phenotyping in capillary DBS is a valid and convenient alternative for the classical plasma-based approach. Additionally, we have provided an objective basis as to why DBS are an ideal tool for CYP1A2 phenotyping

Functional MRI during hippocampal deep brain stimulation in the healthy rat brain

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS

Decision by sampling: the role of the decision environment in risky choice

Decision by sampling (DbS) is a theory about how our environment shapes the decisions that we make. Here, I review the application of DbS to risky decision making. According to classical theories of risky decision making, people make stable transformations between outcomes and probabilities and their subjective counterparts using fixed psychoeconomic functions. DbS offers a quite different account. In DbS, the subjective value of an outcome or probability is derived from a series of binary, ordinal comparisons with a sample of other outcomes or probabilities from the decision environment. In this way, the distribution of attribute values in the environment determines the subjective valuations of outcomes and probabilities. I show how DbS interacts with the real-world distributions of gains, losses, and probabilities to produce the classical psychoeconomic functions. I extend DbS to account for preferences in benchmark data sets. Finally, in a challenge to the classical notion of stable subjective valuations, I review evidence that manipulating the distribution of attribute values in the environment changes our subjective valuations just as DbS predicts

Nonlinear response and discrete breather excitation in driven micro-mechanical cantilever arrays

We explain the origin of the generation of discrete breathers (DBs) in experiments on damped and driven micromechanical cantilever arrays (M.Sato et al. Phys. Rev. Lett. {\bf 90}, 044102, 2003). Using the concept of the nonlinear response manifold (NLRM) we provide a systematic way to find the optimal parameter regime in damped and driven lattices where DBs exist. Our results show that DBs appear via a new instability of the NLRM different from the anticipated modulational instability (MI) known for conservative systems. We present several ways of exciting DBs, and compare also to experimental studies of exciting and destroying DBs in antiferromagnetic layered systems.Comment: 4 pages, 5 figure

Decomposition Based Search - A theoretical and experimental evaluation

In this paper we present and evaluate a search strategy called Decomposition Based Search (DBS) which is based on two steps: subproblem generation and subproblem solution. The generation of subproblems is done through value ranking and domain splitting. Subdomains are explored so as to generate, according to the heuristic chosen, promising subproblems first. We show that two well known search strategies, Limited Discrepancy Search (LDS) and Iterative Broadening (IB), can be seen as special cases of DBS. First we present a tuning of DBS that visits the same search nodes as IB, but avoids restarts. Then we compare both theoretically and computationally DBS and LDS using the same heuristic. We prove that DBS has a higher probability of being successful than LDS on a comparable number of nodes, under realistic assumptions. Experiments on a constraint satisfaction problem and an optimization problem show that DBS is indeed very effective if compared to LDS.Comment: 16 pages, 8 figures. LIA Technical Report LIA00203, University of Bologna, 200

Feasibility of following up gamma-hydroxybutyric acid concentrations in sodium oxybate (Xyrem®)-treated narcoleptic patients using dried blood spot sampling at home : an exploratory study

Background: Gamma-hydroxybutyric acid (GHB), well known as a party drug, especially in Europe, is also legally used (sodium oxybate, Xyrem (R)) to treat a rare sleep disorder, narcolepsy with cataplexy. This exploratory study was set up to measure GHB concentrations in dried blood spots (DBS) collected by narcoleptic patients treated with sodium oxybate. Intra- and inter-individual variation in clinical effects following sodium oxybate administration has been reported. The use of DBS as a sampling technique, which is stated to be easy and convenient, may provide a better insight into GHB concentrations following sodium oxybate intake in a real-life setting. Objective The aim was twofold: evaluation of the applicability of a recently developed DBS-based gas chromatography mass spectrometry (GC MS) method, and of the feasibility of the sampling technique in an ambulant setting. Methods: Seven narcoleptic patients being treated with sodium oxybate at the Department for Respiratory Diseases of Ghent University Hospital were asked to collect DBS approximately 20 min after the first sodium oxybate (Xyrem (R); UCB Pharma Ltd, Brussels, Belgium) intake on a maximum of 7 consecutive days. Using an automatic lancet, patients pricked their fingertip and, after wiping off the first drop of blood, subsequent drops were collected on a DBS card. The DBS cards were sent to the laboratory by regular mail and, before analysis, were visually inspected to record DBS quality (large enough, symmetrically spread on the filter paper with even colouration on both sides of the filter paper). Results: Of the seven patients, three patients succeeded to collect five series of DBS, one patient decided to cease participation because of nausea, one was lost during follow-up and two patients started falling asleep almost immediately after the intake of sodium oxybate. Analysing the DBS in duplicate resulted in acceptable within-DBS card precision. DBS with acceptable quality were obtained by patients without supervision. Conclusion: Our results demonstrate the acceptable precision of the complete procedure, from sampling at home to quantitative analysis in the laboratory. Given the intra-and inter-individual variability in clinical effects seen with sodium oxybate, the easy adaptation of DBS sampling opens the possibility of following up GHB concentrations in patients in real-life settings in future studies

Functional MRI with active, fully implanted, deep brain stimulation systems: Safety and experimental confounds

We investigated safety issues and potential experimental confounds when performing functional magnetic resonance imaging (fMRI) investigations in human subjects with fully implanted, active, deep brain stimulation (DBS) systems. Measurements of temperature and induced voltage were performed in an in vitro arrangement simulating bilateral DBS during magnetic resonance imaging (MRI) using head transmit coils in both 1.5 and 3.0 T MRI systems. For MRI sequences typical of an fMRI study with coil-averaged specific absorption rates (SARs) less than 0.4 W/kg, no MRI-induced temperature change greater than the measurement sensitivity (0.1 °C) was detected at 1.5 T, and at 3 T temperature elevations were less than 0.5 °C, i.e. within safe limits. For the purposes of demonstration, MRI pulse sequences with SARs of 1.45 W/kg and 2.34 W/kg (at 1.5 T and 3 T, respectively) were prescribed and elicited temperature increases (> 1 °C) greater than those considered safe for human subjects. Temperature increases were independent of the presence or absence of active stimulator pulsing. At both field strengths during echo planar MRI, the perturbations of DBS equipment performance were sufficiently slight, and temperature increases sufficiently low to suggest that thermal or electromagnetically mediated experimental confounds to fMRI with DBS are unlikely. We conclude that fMRI studies performed in subjects with subcutaneously implanted DBS units can be both safe and free from DBS-specific experimental confounds. Furthermore, fMRI in subjects with fully implanted rather than externalised DBS stimulator units may offer a significant safety advantage. Further studies are required to determine the safety of MRI with DBS for other MRI systems, transmit coil configurations and DBS arrangements