Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain : A new treatment strategy for neonatal seizures?

Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ--aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB. Methods: In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats. Results: Serum from 1- to 2-day-old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide. Significance: These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add-on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures. © 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epileps

Advanced head models to improve TMS-based motor cortex localization

status: publishe

Optimized preoperative motor cortex mapping in brain tumors using advanced processing of transcranial magnetic stimulation data

BACKGROUND AND OBJECTIVE: Transcranial magnetic stimulation (TMS) is a useful technique to help localize motor function prior to neurosurgical procedures. Adequate modelling of the effect of TMS on the brain is a prerequisite to obtain reliable data. METHODS: Twelve patients were included with perirolandic tumors to undergo TMS-based motor mapping. Several models were developed to analyze the mapping data, from a projection to the nearest brain surface to motor evoked potential (MEP) amplitude informed weighted average of the induced electric fields over a multilayer detailed individual head model. The probability maps were compared with direct cortical stimulation (DCS) data in all patients for the hand and in three for the foot. The gold standard was defined as the results of the DCS sampling (with on average 8 DCS-points per surgery) extrapolated over the exposed cortex (of the tailored craniotomy), and the outcome parameters were based on the similarity of the probability maps with this gold standard. RESULTS: All models accurately gauge the location of the motor cortex, with point-cloud based mapping algorithms having an accuracy of 83-86%, with similarly high specificity. To delineate the whole area of the motor cortex representation, the model based on the weighted average of the induced electric fields calculated with a realistic head model performs best. The optimal single threshold to visualize the field based maps is 40% of the maximal value for the anisotropic model and 50% for the isotropic model, but dynamic thresholding adds information for clinical practice. CONCLUSIONS: The method with which TMS mapping data are analyzed clearly affects the predicted area of the primary motor cortex representation. Realistic electric field based modelling is feasible in clinical practice and improves delineation of the motor cortex representation compared to more simple point-cloud based methods.status: publishe

AEPs to deviant and standard stimuli elicited with a deviant probability of 0.2.

<p>Deviant (black curve) and standard potential (grey curve) with errorbars (standard error of the mean) displayed for four electrodes. Prominent peaks are labeled (P1, N1, P2). Black bar on the x-axis shows the stimulus duration. Below each graph FDR-corrected p-values are shown.</p

Significant differences between standard and deviant deflections with respect to deviant probability.

*<p>p-values are FDR corrected for multiple comparisons.</p

Significant differences between standard and deviant deflections with respect to stimulus duration.

*<p>p-values are FDR corrected for multiple comparisons.</p

Oddball deviant compared to the equiprobable control condition.

<p>Oddball deviant (red curve), control “deviant” (black curve) and oddball standard (blue curve) potentials were elicited with either 0.1 deviant probability (diagrams on the left side) or 0.2 deviant probability (diagrams on the right side). Data is derived from 6 rats. The posterior electrodes on the left and right hemisphere as well as anterior electrodes on the left and right hemisphere were pooled for displaying the results and statistical calculation. Black bar on the x-axis shows stimulus duration. Below each graph FDR-corrected p-values are shown. The black curve displays the differences between oddball deviants and control deviants whereas the blue curve displays significant differences between oddball standard and control deviant.</p

MMN-like activity displayed as difference waveforms for two deviant probabilities.

<p>Difference calculated as deviant minus standard potential displayed for four electrodes. Potentials were elicited using an oddball paradigm with deviant probability 0.1 (black curve) and 0.2 (grey curve). Black bar on the x-axis shows the stimulus duration. Below each graph FDR-corrected p-values are shown.</p