STRUCTURING OF ELECTRODE SURFACES WITH LIGAND-FREE NANOPARTICLES VIA ELECTROPHORETIC DEPOSITION- FUNDAMENTALS AND IN VIVO APPLICATIONS

Electrodes for neural stimulation and recording are highly relevant in modern medicine, e.g. for the treatment of movement disorders. As these electrodes have to be implanted directly into the patient´s brain, impaired biocompatibility as well as reduced performance due to increased impedance upon tissue contact are serious problems. Strategies to improve the efficiency of electrodes entail the implementation of defined nanoscopic structures to the electrode surface, which increase the surface area and improve the current flow by possible edge effects1. In this context electrophoretic deposition (EPD) of nanoparticles (NP) constitutes an efficient and feasible way for surface structuring as in contrast to e.g. ablative laser machining, electric field lines are naturally ordered perpendicular to the implant´s surface, so that electrophoretic deposition is well compatible to shaped implants and curved surfaces. In this work an EPD process for the structuring of Pt electrode surfaces with NP is systematically investigated. Reference NP from a modern synthesis route named pulsed laser ablation in liquids (PLAL)2 are utilized as they possess a high surface charge density in order to ease their movement in an electric field. The electrophoretic velocity of these NP was examined and found to be linearly-correlated with the electric field strength, while the slope is dictated by the NP´s surface charge density (zeta-potential).3, 4 On the other hand the PLAL-generated NP are, by design, completely free of organic ligand, which significantly affected their deposition in an EPD setup. It was found that the deposited mass linearly increased with process time, yielding a well scalable process, while on the other hand control experiments with ligands showed a saturation of the deposited mass due to electrochemical shielding of the surface by charged ligands.4 It was furthermore demonstrated that the EPD process with ligand-free NP could also be done in a continuous flow-through setup suitable for the parallel structuring of multiple electrodes.5 Interestingly, the deposition velocity was not size dependent as particle size distributions prior to and after EPD were identical.5 In consecutive experiments, the surface properties like coverage, oxidation, wettability6 and impedance of the electrode materials were evaluated and correlated with the EPD process parameters electric field strength, colloid concentration and deposition time. As a result a detailed map was obtained, which allows a defined tuning of Pt surface properties by Pt NP EPD. Finally, the impedance of electrodes coated with ligand-free Pt NP were evaluated in long term stimulation experiments with rats. The NP coating could stabilize the impedance of the electrodes in vivo, while it continuously increased in non-coated controls.7 Furthermore, the coated electrodes exhibited excellent biocompatibility similar to the controls7 while no significant NP desorption from the surface was found upon mechanical tear. 1. X. F. F. Wei and W. M. Grill, J. Neural Eng., 2005, 2, 139-147. 2. V. Amendola and M. Meneghetti, Phys. Chem. Chem. Phys., 2013, 15, 3027-3046. 3. A. Menendez-Manjon, J. Jakobi, K. Schwabe, J. K. Krauss and S. Barcikowski, J. Laser Micro Nanoeng., 2009, 4, 95-99. 4. C. Streich, S. Koenen, M. Lelle, K. Peneva and S. Barcikowski, Appl. Surf. Sci., 2015, 348, 92-99. 5. S. Koenen, R. Streubel, J. Jakobi, K. Schwabe, J. K. Krauss and S. Barcikowski, J. Electrochem. Soc., 2015, 162, D174-D179. 6. A. Heinemann, S. Koenen, K. Schwabe, C. Rehbock and S. Barcikowski, Key engineering materials, 2015, 654, 218-223. 7. S. D. Angelov, S. Koenen, J. Jakobi, H. E. Heissler, M. Alam, K. Schwabe, S. Barcikowski and J. K. Krauss, J. Nanobiotechnol., 2016, 14

Neurobiological Mechanisms of Metacognitive Therapy – An Experimental Paradigm

IntroductionThe neurobiological mechanisms underlying the clinical effects of psychotherapy are scarcely understood. In particular, the modifying effects of psychotherapy on neuronal activity are largely unknown. We here present data from an innovative experimental paradigm using the example of a patient with treatment resistant obsessive-compulsive disorder (trOCD) who underwent implantation of bilateral electrodes for deep brain stimulation (DBS). The aim of the paradigm was to examine the short term effect of metacognitive therapy (MCT) on neuronal local field potentials (LFP) before and after 5 MCT sessions.MethodsDBS electrodes were implanted bilaterally with stereotactic guidance in the bed nucleus of the stria terminalis/ internal capsule (BNST/IC). The period between implantation of the electrodes and the pacemaker was used for the experimental paradigm. DBS electrodes were externalized via extension cables, yielding the opportunity to record LFP directly from the BNST/IC. The experimental paradigm was designed as follows: (a) baseline recording of LFP from the BNST/IC, (b) application of 5 MCT sessions over 3 days, (c) post-MCT recording from the BNST/IC. The Obsessive-Compulsive Disorder- scale (OCD-S) was used to evaluate OCD symptoms.ResultsOCD symptoms decreased after MCT. These reductions were accompanied by a decrease of the relative power of theta band activity, while alpha, beta, and gamma band activity was significantly increased after MCT. Further, analysis of BNST/IC LFP and frontal cortex EEG coherence showed that MCT decreased theta frequency band synchronization.DiscussionImplantation of DBS electrodes for treating psychiatric disorders offers the opportunity to gather data from neuronal circuits, and to compare effects of therapeutic interventions. Here, we demonstrate direct effects of MCT on neuronal oscillatory behavior, which may give possible cues for the neurobiological changes associated with psychotherapy

Pseudotumor cerebri syndrome in a child with Alagille syndrome: intracranial pressure dynamics and treatment outcome after ventriculoperitoneal shunting

Alagille syndrome (AS) is a rare multisystem disease of the liver, heart, eyes, face, skeleton, kidneys, and vascular system. The occurrence of pseudotumor cerebri syndrome (PTCS) in patients with AS has been reported only exceptionally. Owning to its rarity and a mostly atypical presentation, the diagnosis and natural history of affected patients remain uncertain. We report an atypical case of PTCS in a 4-year-old boy with a known history of AS who presented with bilateral papilledema (PE) on a routine ophthalmological examination. Visual findings deteriorated after treatment with acetazolamide. Continuous intracranial pressure (ICP) monitoring was then utilized to investigate ICP dynamics. Successful treatment with resolution of PE was achieved after ventriculoperitoneal shunting but relapsed due to growth-related dislocation of the ventricular catheter. This report brings new insights into the ICP dynamics and the resulting treatment in this possibly underdiagnosed subgroup of PTCS patients. It also demonstrates that ventriculoperitoneal shunting can provide long-term improvement of symptoms for more than 10 years

Development of Hyperkinesias after Long-term Pallidal Stimulation for Idiopathic Segmental Dystonia

Background:&nbsp;Chronic deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an established treatment for dystonia. While bradykinetic symptoms may occur on chronic stimulation, the appearance of hyperkinetic movements has not been well characterized.Case Report:&nbsp;We report on the development of hyperkinesias after more than 10 years of GPi DBS.Discussion:&nbsp;Hyperkinesias may evolve upon long-term GPi DBS in dystonia. This might be related to a combined effect consisting of a reduced threshold for effective GPi stimulation for dystonia and spread of current to the globus pallidus externus.&nbsp;</p

Experimental Rat Model for Brain Death Induction and Kidney Transplantation

Background: Experimental animal research has been pivotal in developing clinical kidney transplantation (KTx). One donor-associated risk factor with negative affect of transplantation outcome is brain death (BD). Many rat models for BD and KTx have been developed in the last decade, but no surgical guidelines have been developed for these models. Here, we describe a surgical technique for BD induction and the cuff technique for experimental KTx in rats. Methods: After intubation and mechanically ventilation of sixteen healthy adult male Sprague–Dawley rats were induction of BD performed. Animals were kept hemodynamically stable for eight hours. Then, the kidney was prepared and perfused with standard histidine–tryptophan–ketoglutarate solution. After explantation, grafts were immediately implanted in recipients using the cuff technique and reperfused. After 2 h of observation, animals were sacrificed by intravenous administration of potassium chloride. Results: In the early phase of BD, heart rate increased and mean arterial pressure decreased. Partial variations were observed in O2 partial pressure, O2 saturation, and HCO3. During the 2-h observation phase, all transplanted kidneys were sufficiently perfused macroscopically. There was no hyperacute rejection. Conclusions: It is feasible to observe BD for 8 h with maintained circulation in small experimental settings. The cuff technique for KTx is simple, the complication rate is low, and the warm ischemia time is short, therefore, this could be a suitable technique for KTx in the rat model

Time-course of plasma inflammatory mediators in a rat model of brain death.

BACKGROUND Brain death (BD) is a donor-associated risk factor that negatively affects transplantation outcome. The inflammation associated with BD appears to have a negative effect on organ quality. Complement activation, apoptosis, and pro-inflammatory cytokine and chemokine expression are significantly increased after BD. To better understand this process, we investigated plasma chemokine and cytokine levels for 8h after BD in a rodent model. METHODS Thirteen healthy adult male Sprague Dawley rats were intubated and mechanically ventilated. After induction of BD, animals were kept hemodynamically stable for 8h. A panel of immune response factors, including cytokines and chemokines, were measured immediately prior to the induction of BD and at 1, 4, and 8h after BD by multiplex analyses in 10 rats. RESULTS In the early phase of BD, we observed an increase in heart rate and a decrease in mean arterial pressure. Only limited fluctuations were noted in the partial pressure of O2, O2 saturation, and HCO3. Monocyte-/macrophage- and lymphocyte-derived mediators (IL-2, IL-4, and IFN-γ) increased steadily during the 8-hour monitoring period. CONCLUSIONS The increase in immune responses, particularly pro-inflammatory responses, after BD is time-dependent. Cytokines and chemokines from donors and recipients require further investigation to determine the optimal time frames for organ transplantation in rodent models and humans

Centromedian–Parafascicular and Somatosensory Thalamic Deep Brain Stimulation for Treatment of Chronic Neuropathic Pain: A Contemporary Series of 40 Patients

Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian–parafascicular (CM–Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM–Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3–180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM–Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain