Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.

BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.

Detubulation effects on the action of zinc on frog skeletal muscle action potential.

Detubulation of the untreated fiber decreases the time constant of the action potential's foot (tauf) and increases the maximal rate of rise of the spike (Vmax). Zinc at all concentrations, and regardless of whether the fiber is intact or detubulated, increases tauf and decreases Vmax, and thus seems to decrease Na activation of the fiber. Detubulation was used principally to elucidate the localization and mechanism of the Zn2+-induced retardation of the falling phase of the frog sartorius fiber action potential, which evidently results from a general depression of delayed rectification. At 50 to 1000 mum, Zn2+ not only prolongs repolarization of intact fibers (measured by increase in t0.5, the half-time of the spike's fall), but also produces a marked hump early in this phase. Detubulation of zinc-free fibers reduces t0.5 to about 80% of its intact value, and under Zn2+ treatment t0.5 is increased but only to about 80% of that produced in the inus, detubulation decreases t0.5 in Zn2+-treated fibers not only to about 80% of that produced in the intact fiber, and the falling-phase hump is completely obliterated. Thus, detubulation decreases t0.5 in Zn2+-treated fibers not only by generally eliminating T-tubular participation in action potential generation, but also by subtracting a Zn2+-induced retardation of tubular delayed rectification. Tubular delayed rectification must therefore be an intrinsic feature of normal excitation. These results are further analyzed by means of (i) Stanfield's findings about retardation of delayed rectification by Zn2+ and (ii) Adrian-Peachey's theory of T-tubule participation in action potential generation, which suggests that the Zn2+-evoked repolarization hump signals onset of Zn2+-altered active participation of T-tubules in determining the spike's shape.

Deuterium oxide effects on excitation-contraction coupling of skeletal muscle.

2H2O (99.8%) Ringer's solution greatly reduces the twitch and tetanus of frog sartorius muscle and, as specially shown here, slows the onset features of the mechanical output of the twitch by: (a) increasing the time (LR) from stimulus to start of latency relaxation; (b) slowing the development of the latency relaxation, and (c) greatly decreasing the rate of onset of tension development. These changes reflect effects of 2H2O on excitation-contraction coupling and they represent the critical direct effects of 2H2O on muscle since it does not depress either the action potential or the intrinsic myofibrillar contractility. The increase in LR is attributed to slowed inward electrical propagation in the T-tubule. But the critical effect of 2H2O on frog muscle is to greatly depress mobilization of activator Ca2+. The depression of the Ca2+ mobilization and of its effects on the activation of contraction evidently result from (a) a lowered rate of release of Ca2+ from the sar coplasmic reticulum, as indicated by the slowed development of the latency relaxation, (b) a decreased amount of Ca2+ released in a twitch, and (c) a reduced speed of diffusion of the Ca2+ to the contractile filaments. The depressed mobilization of Ca2+ is apparently the essential cause of 2H2O's general depression of twitch and tetanus output.

Physostigmine-induced contractures in frog skeletal muscle.

Physostigmine in 15 mM concentration at pH 8.4 produces reversible contractures of up to 0.3 Po tension output in frog's whole toe muscle or in 7-10 fiber bundles of these muscles, At pH 7.2, the 15 mM physostigmine contracture output is only about 0.10 Po. The 15 mM, pH 8.4 contractures are essentially unaffected by lack of external Ca2+, complete depolarization of the fibers, detubulation by glycerol treatment, and 0 degrees C ambient temperature. These results and other evidence indicate that physostigmine produces contracture by directly releasing activator Ca2+ from the sarcoplasmic reticulum (SR). Pretreatment of muscles with 4 mM procaine reduces physostigmine's capacity to produce contracture, evidently by means of a competitive inhibition at SR sites. The above results indicate similarities between physostagmine and caffeine contractures. But the physostigmine action differs in that it is reversible, and, especially, it lacks the ability, strongly characteristic of caffeine, to sensitize a muscle to produce a rapid cooling contracture. The internal action of physostigmine requires that it be permeant, and, since it is a weak base (pKa = 8.2), this property is provided by its uncharged base. But, once internal, where the pH = 6.8, most of the drug will be protonated and it may act on the SR in this form, in contrast with caffeine which, since its pKa is about 1.0, acts on the SR as uncharged base.

Twitch potentiation of skeletal muscle by physostigmine at different pH.

This report extends earlier research, done with external media at pH 7.2, to new studies at pH 6.4 and 8.4 as well as 7.2, to determine the roles of the protonated and neutral forms of physostigmine (a weak base with pKalpha = 8.2) in causing twitch potentiation of the frog sartorius muscle. Physostigmine, especially at relatively high pH (8.4) and concentration (1.5 mM), considerably blocks excitation. However, the results show in general that physostigmine potentiation increased peak contraction time and thereby indicate that potentiation is occurring in terms of prolongation of the active state. At pH 6.4 and 8.4, 1 mM physostigmine causes no change in the mechanical threshold of K depolarization contractures of toe muscles, as found previously at pH 7.2. Physostigmine increasingly prolongs the action potential as pH rises, i.e., in positive correlation with the twitch potentiation, thus indicating that this electrical change is the prime determinant of the potentiation.

Excitation-contraction coupling: effects of "zero"-Ca2+ medium.

Frog sartorius muscles, exposed for up to 15--20 min to media containing ethylene glycol bis (beta-aminoethyl ether) - N, N'-tetraacetic acid and thus having free Ca2+ concentration less than 10(-8) M, produce isometric contractions with basically normal but speedier latency relaxation and earliest tension development. The excitation-contraction coupling is thus also basically normal, but speedier evidently in respect to release of activator Ca2+ from the sarcoplasmic reticulum.

Contractures in partially depolarized muscle treated with caffeine or nitrate.

Frog toe muscles partially depolarized with a subcontracture concentration (15 or 20mM) of K+ rapidly developed tension when exposed to 1 mM caffeine, which alone did not cause contracture. This action resulted from a lowering of the mechanical threshold by the caffeine and thus was similar to that caused by replacement of Cl- with NO3-. Maximal tension was the same in the caffeine and NO3- media but took much longer to develop in the former. Equilibrating the muscles with caffeine for 60 s (the time calculated for complete diffusion) did not reduce contraction time significantly. However, prolonging the exposure of muscles to caffeine beyond this time enhanced the drug's capacity to potentiate both the twitch and 30 mM K+ contractures and shortened the contraction time of the contractures. Toe muscles that had undergone a contracture in 100 mM K+ and were recovering in 15 mM K+-Ringer generated tension in the presence of 1 mM caffeine or NO3- but only after enough repolarization had been achieved so that a response to a second challenge with 100 mM K+ could be demonstrated. Although prolonged immersion in the K+-enriched recovery solution caused a disappearance of sensitivity to a test depolarization, addition of 1 mM caffeine or replacement of Cl- with NO3- promptly evoked a contracture. These results imply a reversible step in the recovery process that is both potential and time dependent. Since application of 5 mM caffeine to either normally polarized or depolarized muscles always immediately causes contracture, more than one site of action for caffeine is indicated. After disruption of the transverse tubules, partially depolarized muscles showed no response to NO3- or 1 mM caffeine but contracted vigorously when exposed to 5 mM caffeine.

Action potential parameters affecting excitation-contraction coupling.

In quantifying type B potentiation effects, given earlier merely qualitatively, it is found that Zn(2+), 1-50 microM, causes increases in action potential duration, twitch tension, and twitch contraction period time, which are all directly proportional to the log of the concentration. Hence, the duration of the action potential, i.e. the magnitude of its mechanically effective period, is a causal factor quantitatively determining the degree of mechanical activation in the isometric twitch. In higher concentrations of Zn(2+) up to 1000 microM, the spike duration and the contraction time continue to increase but the twitch tension is disproportionately smaller, evidently because the high zinc (500-1000 microM) raises the mechanical threshold of excitation-contraction (E-C) coupling and reduces the intrinsic strength of the contractile system. Eserine (1.5 mM) and also high Zn(2+) not only cause type B potentiation effects, but also slow the rise of the spike, thus causing retardation of the very onset of tension production, which is even greater for high Zn(2+) because of the raised mechanical threshold. This retardation is then succeeded by the faster tension output characteristic of type B potentiation resulting from spike prolongation. Thus, the changes in the consecutive, rising and falling phases of the action potential explicitly register their separate effects in the respective very earliest and directly following periods of twitch output; i.e., each phase of the action potential produces its own mechanical "transform." These transforms, and other effects, suggest that the release of activator Ca(2+) from the sarcoplasmic reticulum during E-C coupling can be graded in both the rate and the total amount of the release.

Mechanical threshold as a factor in excitation-contraction coupling.

I(-), CH(3)SO(4) (-), and ClO(4) (-), like other previously studied type A twitch potentiators (Br(-), NO(3) (-), SCN(-), and caffeine), lower the mechanical threshold in K depolarization contractures of frog skeletal muscle. In potentiated twitches, I(-), Br(-), CH(3)SO(4) (-), ClO(4), and SCN, as already reported for NO(3) (-) and caffeine, slightly shorten the latent period (L) and considerably increase the rate of tension development (dP/dt) during the first few milliseconds of the contraction period. Divalent cations (8 mM Ca(2+), 0.5-1.0 mM Zn(2+) and Cd(2+)) raise the mechanical threshold of contractures, and correspondingly affect the twitch by depressing the tension output, increasing L, and decreasing the early dP/dt, thus acting oppositely to the type A potentiators. These various results form a broad, consistent pattern indicating that electromechanical coupling in the twitch is conditioned by a mechanical threshold as it is in the contracture, and suggesting that the lower the threshold, in reference to the raised threshold under the action of the divalent cations, the more effective is a given action potential in activating the twitch as regards especially both its early rate and peak magnitude of tension development. The results suggest that the direct action by which the various agents affect the level of the mechanical threshold involves effects on E-C coupling processes of the T tubular and/or the sarcoplasmic reticulum which control the release of Ca for activating contraction.

Quinine and caffeine effects on 45Ca movements in frog sartorius muscle.

1 mM caffeine, which produces only twitch potentiation and not contracture in frog sartorius muscle, increases both the uptake and release of (45)Ca in this muscle by about 50 %, thus acting like higher, contracture-producing concentrations but less intensely. Quinine increases the rate of release of (45)Ca from frog sartorius but not from the Achilles tendon. The thresholds for the quinine effect on (45)Ca release and contracture tension are about 0.1 and 0.5 mM, respectively, at pH 7.1. Quinine (2 mM) also doubles the uptake of (45)Ca by normally polarized muscle. However, there are variable effects of quinine upon (45)Ca uptake in potassium-depolarized muscle. Quinine (2 mM), increases the Ca, Na, and water content of muscle while decreasing the K content. Both caffeine (1 mM) and quinine (2 mM) act to release (45)Ca from muscles that have been washed in Ringer's solution from which Ca was omitted and to which EDTA (5 mM) was added. These results, correlated with those of others, indicate that a basic effect of caffeine and quinine on muscle is to directly release activator Ca(2+) from the sarcoplasmic reticulum in proportion to the drug concentration. The drugs may also enhance the depolarization-induced Ca release caused by extra K(+) or an action potential. In respect to the myoplasmic Ca(2+) released by direct action of the drugs, a relatively high concentration is required to activate even only threshold contracture, but a much lower concentration, added to that released during excitation-contraction coupling, is associated with the condition causing considerable twitch potentiation.