Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation

Objective

Clinical deep brain stimulation (DBS) systems typically utilize voltage-controlled stimulation and thus the voltage distribution generated in the brain can be affected by electrode impedance fluctuations. The goal of this study was to experimentally evaluate the theoretical advantages of using current-controlled pulse generators for DBS applications.

Methods

Time-dependent changes in the voltage distribution generated in the brain during voltage-controlled and current-controlled DBS were monitored with in vivo experimental recordings performed in non-human primates implanted with scaled-down clinical DBS electrodes.

Results

In the days following DBS lead implantation, electrode impedance progressively increased. Application of continuous stimulation through the DBS electrode produced a decrease in the electrode impedance in a time dependent manner, with the largest changes occurring within the first hour of stimulation. Over that time period, voltage-controlled stimuli exhibited an increase in the voltage magnitudes generated in the tissue near the DBS electrode, while current-controlled DBS showed minimal changes.

Conclusion

Large electrode impedance changes occur during DBS. During voltage-controlled stimulation, these impedance changes were significantly correlated with changes in the voltage distribution generated in the brain. However, these effects can be minimized with current-controlled stimulation.

Significance

The use of current-controlled DBS may help minimize time-dependent changes in therapeutic efficacy that can complicate patient programming when using voltage-controlled DBS.     

Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin

Background

Warfarin is routinely used in the prevention and treatment of prothrombotic events. During initiation of warfarin therapy levels of factor (F) VII and protein C decrease rapidly but prothrombin, FIX and FX decline much slower. Therefore, propagation of thrombin generation (TG) remains unaffected much longer, increasing the risk of inadequate anticoagulation. Recently, a novel agent, anti-IXa aptamer, RB006, has been developed. Therefore, we have evaluated the in vitro effects of this agent in warfarin plasma.

Methods

The investigation consisted of two parts. First, a computer simulated time course of TG with warfarin alone and in combination with FIXa inhibition was evaluated and, second, normal volunteer, protein C deficient, FVII deficient and commercial warfarin plasmas (INR 2.1 and 3.1) were spiked with increasing concentrations of aptamer (0-24 µg/ml) and its anticoagulant effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT) and TG with tissue factor and Actin as activators. Direct effects of aptamer on protein C were also evaluated.

Results

Simulation of coagulation during warfarin induction showed that TG can be significantly delayed and decreased by inhibiting FIXa (i.e., with anti-FIXa aptamer). The anti-FIXa aptamer inhibited TG in all tested plasmas, but was most efficacious in warfarin and FVII deficient plasma. The aptamer itself did not inhibit protein C and had no effect on PT, but concentration-dependently increased aPTT.

Conclusion

The anti-FIXa aptamer potentiates the inhibitory effects of warfarin on TG, and may fill the need as an adjuvant agent during initiation of warfarin therapy.     

Technical Report The effect of pancuronium on the solubility of aqueous thiopentone

In this study we identified the precipitate formed when pancuronium bromide (pH 3.9) and sodium thiopentone (pH 10.6) are combined in vitro. A precipitate formed when sufficient pancuronium was added to thiopentone to decrease the pH below 9.25. The precipitate was isolated, redissolved in alkaline solution and identified as thiopentone using ultraviolet spectrophotometry. Pancuronium was soluble in water in the pH range of 2.0 to 12.0, whereas thiopentone was soluble in water only at a pH greater than 9.90. We conclude that thiopentone precipitates when combined with pancuronium because of a pH-dependent decrease in the solubility of thiopentone, rather than a chemical interaction.     

Nickel-magnesium interactions in carcinogenesis: dose effects and involvement of natural killer cells

The effects of magnesium carbonate (MgCarb) on carcinogenesisand natural killer (NK) cell modulation by nickel subsulfide(NI₃S₂) were studied. Male Fischer F344/NCr rats, 50–90g body wt, 20 rats per group, received single i.m. injectionsinto both thigh muscles of 2.5 mg Ni3S2 alone or combined withdifferent proportions of MgCarb; the Mg/Ni molar ratio rangedfrom 0.25 to 4.0. Control rats received i.m. injections of normalsaline or magnesium acetate (MgAcet), or s.c. MgCarb at a sitedistant from Ni₃S₂. The animals were observed over 79 weeksfor the development of tumors. The NK cell activity was determinedover the first 3 weeks of the experiment in separate groupsof rats treated as above, with the use of the ⁵¹Cr/YAC-1 releaseassay for blood and spleen cells and the peroxidase localizationof Ox-8-immunoreactive lymphocytes at the injection site. I.m.administration of MgCarb mixed with Ni₃S₂ up to the Mg/Ni molarratio of 1.0 inhibited the carcinogenicity of Ni₃S₂ in a dose-relatedmanner; final incidence of sarcomas decreased from 100 to 55%and the appearance of first tumors was delayed from 25 to 39weeks. Higher doses of MgCarb did not exert further effect.Distant s.c. injection of MgCarb or local i.m. application ofMgAcet did not change the carcinogenic potency of i.m. Ni₃S₂.MgCarb or saline alone did not produce any tumors. I.m. Ni₃S₂had no significant influence on the activity of NK cells inblood and spleen, while i.m. MgCarb alone did not affect theNK activity in blood but doubled it transiently in the spleen24 h after injection. In the injected muscle, Ox-8-positivecells became abundant around MgCarb but could not be found closeto Ni₃S₂. This inhibitory effect of Ni₃S₂ was partially reversedby MgCarb. Also, numerous multinucleated giant cells infiltratedthe sites of injection of MgCarb alone and MgCarb + Ni₃S₂ butnot Ni₃S₂ alone. The results indicate a dose-dependent and strictlylocal character of the inhibition by MgCarb of Ni₃S₂ carcinogenesis,as well as a possible involvement of NK and phagocytic cellsin this inhibition.