Physiological Bases of Magnetoencephalography and Electroencephalography

Understanding the physiological bases of magnetoencephalography (MEG) and electroencephalography (EEG) provides the foundation for developing these techniques as tools for studying human brain functions because this information can serve as a guide for planning experimental studies and for interpreting the data. During the past 50 years, the concept of electrophysiology of neurons has been profoundly modified as new types of active conductance have been discovered in the dendrites and soma. The biophysical models of individual neurons and neuronal networks developed within the framework of modern electrophysiology have provided quantitatively accurate accounts of evoked magnetic fields, extracellular potentials, and intracellular potentials in principal neurons in the tissues within a single theoretical framework. These results are consistent with the conclusion that intracellular currents in active tissues produce both MEG and EEG signals in the cerebellum, hippocampus, and cerebral cortex. We now know that the calcium and potassium currents are the major currents shaping the waveforms of MEG and EEG and that the sodium and potassium currents generate the spikes and high-frequency signals detectable outside the brain. The current dipole moment density, defined as current dipole moment per unit surface area of the active cortex, is governed by the intracellular volume fraction and basic kinetics of the active conductances. This quantity, which is conserved across the evolutionary scale ranging from reptiles to humans, may serve as a useful physiological constraint in interpreting MEG and EEG signals. It is hoped that this foundation will help advance the research on human brain functions.

CaMKII inhibition hyperpolarizes membrane and blocks nitrergic IJP by closing a Cl− conductance in intestinal smooth muscle

The ionic basis of nitrergic “slow'” inhibitory junction potential (sIJP) is not fully understood. The purpose of the present study was to determine the nature and the role of calmodulin-dependent protein kinase II (CaMKII)-dependent ion conductance in nitrergic neurotransmission at the intestinal smooth muscle neuromuscular junction. Studies were performed in guinea pig ileum. The modified Tomita bath technique was used to induce passive hyperpolarizing electrotonic potentials (ETP) and membrane potential change due to sIJP or drug treatment in the same cell. Changes in membrane potential and ETP were recorded in the same smooth muscle cell, using sharp microelectrode. Nitrergic IJP was elicited by electrical field stimulation in nonadrenergic, noncholinergic conditions and chemical block of purinergic IJP. Modification of ETP during hyperpolarization reflected active conductance change in the smooth muscle. Nitrergic IJP was associated with decreased membrane conductance. The CAMKII inhibitor KN93 but not KN92, the Cl− channel blocker niflumic acid (NFA), and the KATP-channel opener cromakalim hyperpolarized the membrane. However, KN93 and NFA were associated with decreased and cromakalim was associated with increased membrane conductance. After maximal NFA-induced hyperpolarization, hyperpolarization associated with KN93 or sIJP was not seen, suggesting a saturation block of the Cl− channel signaling. These studies suggest that inhibition of CaMKII-dependent Cl− conductance mediates nitrergic sIJP by causing maximal closure of the Cl− conductance.

Synaptic Background Activity Enhances the Responsiveness of Neocortical Pyramidal Neurons

Neocortical pyramidal neurons in vivo are subject to an intense synaptic background activity but little is known of how this activity affects cellular responsiveness and what function it may serve. These issues were examined in morphologically reconstructed neocortical pyramidal neurons in which synaptic background activity was simulated based on recent measurements in cat parietal cortex. We show that background activity can be decomposed into two components: a tonically active conductance and voltage fluctuations. Previous studies have mostly focused on the conductance effect, revealing that background activity is responsible for a decrease in responsiveness, which imposes severe conditions of coincidence of inputs necessary to discharge the cell. It is shown here, in contrast, that responsiveness is enhanced if voltage fluctuations are taken into account; in this case the model can produce responses to inputs that would normally be subthreshold. This effect is analyzed by dissecting and comparing the different components of background activity, as well as by evaluating the contribution of parameters such as the dendritic morphology, the distribution of leak currents, the value of axial resistivity, the densities of voltage-dependent currents, and the release parameters underlying background activity. Interestingly, the model's optimal responsiveness was obtained when voltage fluctuations were of the same order as those measured intracellularly in vivo. Possible consequences were also investigated at the population level, where the presence of background activity allowed networks of pyramidal neurons to instantaneously detect inputs that are small compared with the classical detection threshold. These results suggest, at the single-cell level, that the presence of voltage fluctuations has a determining influence on cellular responsiveness and that these should be taken into account in models of background activity. At the network level, we predict that background activity provides the necessary drive for detecting events that would normally be undetectable. Experiments are suggested to explore this possible functional role for background activity.

Effect of furosemide on the electrical parameters of frog skin

When added to the mucosal solution bathing isolated frog skin at concentrations ranging from 5 X 10(-4) to 3 X 10(-3) M, the diuretic furosemide increased both the active transport of sodium and the electrical potential difference across the tissue in a dose-dependent way. The same effect was observed in chloride-free solutions. Mucosal furosemide also decreased the passive unidirectional fluxes of chloride. We believe that as far as electrical parameters are concerned mucosal furosemide has a double effect in frog skin: it increases the active conductance to sodium across the mucosal membrane, thus increasing active transport, and decreases the passive permeability to chloride, thus altering the passive conductance of the skin. The relative increase in short-circuit current was, however, invariably greater than the increase of the active conductance, suggesting the influence of yet a third effect. The effect of mucosal furosemide on active sodium transport was blocked by amiloride (5 X 1-(-5) M) and was independent of vasopressin. Qualitatively the effect was similar to the effect produced by triphenylmethylphosphonium ion.

Effect of furosemide on the thermodynamic parameters of frog skin

The formalism of nonequilibrium thermodynamics (NET) was used to analyze the effect of diuretic furosemide on the transport mechanism of frog skin. Mucosal furosemide increased the active conductance of Na+ across the mucosal membrane of the cells, producing an increased transport of Na+ (short-circuit current). Furosemide also increased both the thermodynamic affinity of the metabolic reaction supplying energy to the sodium pump and the degree of coupling between transport and metabolism. It changed the phenomenological cross-coefficient of the NET description as well as the stoichiometric ratio, indicating that its effect cannot be explained simply on the basis of a change in Na+ conductance. The effect on the NET parameters was independent of the presence of either chloride or sulfate as the principal anion in the solutions, and was qualitatively similar to the effect produced by mucosal application of triphenylmethylphosphonium ion.

Tetracycline-induced inhibition of Na+ transport in the toad urinary bladder

The effects of three tetracyclines, demethylchlortetracycline (DMC), minocycline (MNC), and oxytetracycline (OTC), on Na+ transport (measured as short-circuit current) were examined in toad urinary bladders mounted in modified Ussing chambers. During a 1-h incubation period serosal DMC (but not MNC or OTC) inhibited basal Na+ transport, whereas MNC (but not DMC or OTC) inhibited ADH-stimulated Na+ transport. MNC also inhibited cyclic AMP-stimulated Na+ transport. During longer incubation periods all three drugs inhibited basal Na+ transport. The DMC-induced inhibition of basal Na+ transport and the MNC-induced inhibition of ADH-stimulated Na+ transport were paralleled by an inhibition of the active conductance of the bladders. Thus, although all three drugs inhibit basal Na+ transport, only MNC inhibits ADH-stimulated Na+ transport. This effect does not correlate with the known effects of the tetracyclines on ADH-stimulated water flow or with drug-protein binding, and may be related to the greater lipid solubility of MNC.

Transport of H+ against electrochemical gradients in turtle urinary bladder

Active H+ transport (JH) by the isolated turtle bladder was inhibited by either an applied chemical gradient (deltapH) or an electrical gradient (deltapsi). The relation of JH to either deltapH or deltapsi was linear, and the slopes and the force gradients required to bring JH to zero were similar with both methods. The transport system was analyzed in terms of an equivalent circuit model comprising a proton motive force (PMF), an active conductance (LH) in series with the pump, and a parallel or passive conductance which may be ignored in this preparation. Increasing ambient PCO2 markedly increased JH and the active conductance (as deltaJH/deltadeltapH) but had no effect on the apparent PMF (PMF'). Similarly, acetazolamide caused comparable decreases in JH and LH without change in PMF'. Inhibition of metabolism by deoxygenation, deoxy-D-glucose, or depletion of metabolic substrate caused large decreases in JH and LH with reduction in PMF' of less than 14%. Glucose addition increased JH and LH but caused a slight decrease in PMF'. Thus, the experimental maneuvers affected the transport rate primarily through changes in the active conductance. Since PMF' was little affected, the force of the pump must be determined by factors other than the metabolic driving reaction alone. Conductance factors relating to transport as well as to metabolism participate in controlling PMF.