Biomedical subjects

Jan Thöne

Publications and source records attributed to Jan Thöne.

3 recordsLinked to original sources

PubMed2007

Non-normality and transformations of random fields, with an application to voxel-based morphometry.

Parametric tests of linear models for images modeled as random fields are based like ordinary univariate tests on distributional assumptions. It is here shown that the effect of departures from assumptions in random field tests is more pronounced than in the univariate condition. Simulations are presented investigating in detail the influence of smoothing, unbalancedness and leverages on empirical thresholds. In certain conditions, significance tests may become invalid. As a case study, the existence and effect of departures from normality of gray matter probability maps, commonly used in voxel-based morphometry, is investigated, as well as the effect of different transformation strategies involving estimating the degree of transformation from the data by maximum likelihood. The best results are achieved with a voxel-by-voxel transformation, suggesting heterogeneity of distributional form across the volume for this kind of data.

Adult↗

PubMed2004

Levetiracetam inhibits Na+-dependent Cl-/HCO3- exchange of adult hippocampal CA3 neurons from guinea-pigs.

The novel anticonvulsant levetiracetam (LEV) was tested for effects on bioelectric activity and intracellular pH (pHi) regulation of hippocampal CA3 neurons from adult guinea-pigs. In 4-aminopyridine-treated slices, LEV (10-100 microm) reduced the frequency of action potentials and epileptiform bursts of CA3 neurons by 30-55%, while the shape of these potentials remained largely unchanged. Suppressive effects were reversed by an increase of pHi with trimethylamine (TMA). Using BCECF-AM-loaded slices, we found that LEV (10-50 microm) reversibly lowered neuronal steady-state pHi by 0.19 +/- 0.07 pH units in the presence of extracellular CO2/HCO3- buffer. In the nominal absence of extracellular CO2/HCO3- or in Na+-free CO2/HCO3(-)-buffered solution, LEV had no effect on steady-state pHi. Recovery of pHi subsequent to ammonium prepulses remained unchanged in the absence of CO2/HCO3- buffer, but was significantly reduced by LEV in the presence of CO2/HCO3- buffer. These findings show that LEV inhibits HCO3(-)-dependent acid extrusion, but has no effect on Na+/H+ exchange. LEV did not affect Na+-independent Cl-/HCO3- exchange because intracellular alkalosis upon withdrawal of extracellular Cl- remained unchanged. These data show that LEV at clinically relevant concentrations inhibits Na+-dependent Cl-/HCO3- exchange, lowers neuronal pHi, and thereby may contribute to its anticonvulsive activity.

Action Potentials↗

PubMed2004

Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3- exchange.

Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4-aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered solution, TPM (25-50 microm) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance. Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization. TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by 0.18+/-0.07 pH units in CO(2)/HCO(3)(-)-buffered solution. Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery. These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid. Alkalosis upon withdrawal of extracellular Cl(-) was augmented by TPM. Furthermore, at decreased pHi due to the absence of extracellular Na(+), TPM reversibly increased pHi. These findings demonstrate that TPM modulates Na(+)-independent Cl(-)/HCO(3)(-) exchange. In the nominal absence of extracellular CO(2)/HCO(3)(-) buffer, both steady-state pHi and firing of epileptiform bursts remained unchanged upon adding TPM. However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA. Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na(+)-independent Cl(-)/HCO(3)(-) exchange and CA. The apparent decrease of steady-state pHi may contribute to the anticonvulsive property of TPM.

Action Potentials↗