Hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) can occur in patients following acute ischaemic stroke in the form of hemorrhagic transformation, and results in significant long-term morbidity and mortality. Anticoagulation theoretically increases risk. We evaluated stroke patients with an indication for anticoagulation to determine the factors associated with hemorrhagic transformation. METHODS: Three-hundred and forty-five patients with ICD-9 codes indicating: (i) acute ischaemic stroke; and (ii) an indication for anticoagulation were screened. One-hundred and twenty-three met inclusion criteria. Data were collected retrospectively. Neuroimaging was reviewed for infarct volume and evidence of ICH. Hemorrhages were classified as: hemorrhagic conversion (petechiae) versus intracerebral hematoma (a space occupying lesion); symptomatic versus asymptomatic. Using multivariable logistic regression, we determined the hypothesized factors associated with intracerebral bleeding. RESULTS: Age [odds ratio (OR) = 1.50 per 10-year increment, 95% confidence interval (CI) 1.07-2.08], infarct volume (OR = 1.10 per 10 ccs, 95% CI 1.06-1.18) and worsening category of renal impairment by estimated glomerular filtration rate (eGFR; OR = 1.95, 95% CI 1.04-3.66) were predictors of hemorrhagic transformation. Ninety- nine out of 123 patients were anticoagulated. Hemorrhage rates of patients on and off anticoagulation did not differ (25.3% vs. 20.8%; P = 0.79); however, all intracerebral hematomas (n = 7) and symptomatic bleeds (n = 8) occurred in the anticoagulated group. CONCLUSIONS: The risk of hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation is multifactorial, and most closely associated with an individual's age, infarct volume and eGFR.

Safe taste memory consolidation is disrupted by a protein synthesis inhibitor in the nucleus accumbens shell.

Consolidation is the process by which a new memory is stabilized over time, and is dependent on de novo protein synthesis. A useful model for studying memory formation is gustatory memory, a type of memory in which a novel taste may become either safe by not being followed by negative consequences (attenuation of neophobia, AN), or aversive by being followed by post-digestive malaise (conditioned taste aversion, CTA). Here we evaluated the effects of the administration of a protein synthesis inhibitor in the nucleus accumbens (NAc) shell for either safe or aversive taste memory trace consolidation. To test the effects on CTA and AN of protein synthesis inhibition, anisomycin (100microg/microl) was bilaterally infused into the NAc shell of Wistar rats' brains. We found that post-trial protein synthesis blockade impaired the long-term safe taste memory. However, protein synthesis inhibition failed to disrupt the long-term memory of CTA. In addition, we infused anisomycin in the NAc shell after the pre-exposure to saccharin in a latent inhibition of aversive taste. We found that the protein synthesis inhibition impaired the consolidation of safe taste memory, allowing the aversive taste memory to form and consolidate. Our results suggest that protein synthesis is required in the NAc shell for consolidation of safe but not aversive taste memories, supporting the notion that consolidation of taste memory is processed in several brain regions in parallel, and implying that inhibitory interactions between both taste memory traces do occur.

Calcium-containing electron-dense structures in the axons of the squid giant synapse.

Following the Oschman and Wall technique, electron-dense structures (EDS) were found on unstained, unosmicated membranes of squid giant synapse axons. These densities contain high concentrations of calcium and phosphorus as identified by energy dispersive X-ray analysis. Based on the signal strength, the quantity is significantly greater than that of other regions of the membrane or tissue spaces. The calcium EDS occur as plaques or globules along the axonic membrane, and small globules are found between sheath cell processes. EDS also occur at the synaptic site. These densities were correlated with the opacity change seen in giant axons. It is proposed that these structures represent sites where the calcium-binding protein found by other investigators has become nearly saturated with calcium.

Specialized membrane junctions between neurons in the vertebrate cerebellar cortex.

"Gap" junctions, the morphological correlate for low-resistance junctions, are demonstrated between some mossy fiber terminals and granule cell dendrites in some lower vertebrate cerebella (gymnotid and frog). Most of the gap junctions (GJs) seen in the gymnotid-fish cerebellum exhibit an asymmetrical configuration, the electron-opaque cytoplasmic material underlying the junction being more extensive in the dendritic than in the axonal side. In the frog cerebellum, the GJs have a symmetrical distribution of such electron-opaque material. In both species the GJs are encountered at the same synaptic interface as the conventional synaptic zone (CSZ), constituting "mixed synapses" in a morphological sense. The axonal surface covered by CSZs is larger than that covered by GJs. In mammalian cerebellum, GJs are observed only in the molecular layer, between perikarya, dendrites, or perikarya and dendrites of the inhibitory interneurons. These GJs are intermixed with attachment plates and intermediary junctions interpreted as simply adhesive. In the mammalian cerebellum, a new type of junction which resembles the septate junctions (SJs) of invertebrate epithelia is observed between axonal branches forming the tip of the brush of basket fibers around the initial segment of the Purkinje cell axon. It is suggested that such junctions may be modified forms of septate junctions. The physiological implications of the possible existence of high-resistance cross-bridges between basket cell terminals, which may compartmentalize the extracellular space and thus regulate extracellular current flow, must be considered.

The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function.

This article reviews the electroresponsive properties of single neurons in the mammalian central nervous system (CNS). In some of these cells the ionic conductances responsible for their excitability also endow them with autorhythmic electrical oscillatory properties. Chemical or electrical synaptic contacts between these neurons often result in network oscillations. In such networks, autorhythmic neurons may act as true oscillators (as pacemakers) or as resonators (responding preferentially to certain firing frequencies). Oscillations and resonance in the CNS are proposed to have diverse functional roles, such as (i) determining global functional states (for example, sleep-wakefulness or attention), (ii) timing in motor coordination, and (iii) specifying connectivity during development. Also, oscillation, especially in the thalamo-cortical circuits, may be related to certain neurological and psychiatric disorders. This review proposes that the autorhythmic electrical properties of central neurons and their connectivity form the basis for an intrinsic functional coordinate system that provides internal context to sensory input.

Frog cerebellum: absence of long-term inhibition upon Purkinje cells.

Electrophysiological studies of the cerebellar cortex of the frog demonstrate a lack of long-term inhibition upon the Purkinje cells. This lack of inhibition correlates well with the absence of stellate and basket cells in the molecular layer of this cerebellum and strongly supports the idea that these interneurones are the agents responsible for the prolonged inhibition seen in the Purkinje cells of other species.

Microdomains of high calcium concentration in a presynaptic terminal.

Increases in intracellular calcium concentration are required for the release of neurotransmitter from presynaptic terminals in all neurons. However, the mechanism by which calcium exerts its effect is not known. A low-sensitivity calcium-dependent photoprotein (n-aequorin-J) was injected into the presynaptic terminal of the giant squid synapse to selectively detect high calcium concentration microdomains. During transmitter release, light emission occurred at specific points or quantum emission domains that remained in the same place during protracted stimulation. Intracellular calcium concentration microdomains on the order of 200 to 300 micromolar occur against the cytoplasmic surface of the plasmalemma during transmitter secretion, supporting the view that the synaptic vesicular fusion responsible for transmitter release is triggered by the activation of a low-affinity calcium-binding site at the active zone.

Preferred centripetal conduction of dendritic spikes in alligator Purkinje cells.

Dendritic action potentials in alligator Purkinje cells tend to have a unidirectional preference which favors centripetal over centrifugal propagation. This unidirectional tendency funnels the peripherally evoked dendritic spikes into the lower dendrites and soma of these cells, and it allows the peripheral dendritic branches to operate to a certain extent as partially independent functional units.

Calcium transient in presynaptic terminal of squid giant synapse: detection with aequorin.

Microinjection of aequorin, a bioluminescent protein sensitive tocalcium, into the presynaptic terminal of the squid giant synapse demnonstrated an increase in intracellular calcium ion concentration during repetitive synaptic transmission. Although no light flashes synchronous with individual presynaptic : tion potentials were detected, the results are considered consistent with the hypothesis that entry of calcium into the presynaptic terminal triggers release of e synaptic transmitter substance.

Cerebellar Purkinje cell projection to the peripheral vestibular organ in the frog.

Neurones located 200 to 300 microns from the surface of the auricular lobe of the frog cerebellar cortex, and identified as Purkinje cells, were activated antidromically from the eighth cranial nerve. A parallel anatomical study confirmed the existence of this projection. On the basis of these findings the existence of a cerebello-vestibular efferent system is postulated, the precise significance of which is as yet unclear. However, since Purkinje cells in other species have an inhibitory action on their target cells, the Purkinje efferent system to the vestibular organ may have an action similar to that ascribed to the olivo-cochlear bundle upon the cochlea, that is, to serve as an inhibitory control system.

Dendritic spikes and their inhibition in alligator Purkinje cells.

Alligator Purkinje cells generate action potentials in the peripheral dendritic tree, after synaptic depolarization via superficial parallel fibers. These action potentials are inhibited at the dendrite level by preceding parallel-fiber volleys at close intervals. We conclude that this inhibition is produced by the activation of the inhibitory interneurons of the molecular layer, the stellate cells, which establish synaptic contacts with the dendrites of the Purkinje cells.

Inferior olive: its role in motor learing.

Specific chemical lesion of the rat inferior olive by intraperitoneal administration of 3-acetylpyridine prevents recuperation from motor abnormalities generated by unilateral labyrinthine lesion. Moreover, in animals that have recuperated from the balyrinthine lesion, 3-acetylpyridine produces a reversal of the symptoms within 2 hours of administration. These results indicate that the integrity of the olivo-cerebellar system is necessary for the acquisition and retention of this form of motor learning, but that the cerebellum itself is not the seat of such learning.

Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice.

Microfluorometric imaging was used to study the correlation of intracellular calcium concentration with voltage-dependent electrical activity in guinea pig cerebellar Purkinje cells. The spatiotemporal dynamics of intracellular calcium concentration are demonstrated during spontaneous and evoked activity. The results are in agreement with hypotheses of dendritic segregation of calcium conductances suggested by electrophysiological experiments. These in vitro slice fluorescence imaging methods are applicable to a wide range of problems in central nervous system biochemical and electrophysiological functions.

[Mathematical interpretation of the switching over between the regimes of electrical activity of the brain].

The switching between the brain functioning regimes, which is indicated by the data of magnetic encephalography, has been modeled. A mathematical model has been constructed in which the switching process occurs without any external influence and may correspond to switches in the brain in pathology.

P-type calcium channels in the somata and dendrites of adult cerebellar Purkinje cells.

The pharmacological and single-channel properties of Ca2+ channels were studied in the somata and dendrites of adult cerebellar Purkinje cells. The Ca2+ channels were exclusively of the high threshold type: low threshold Ca2+ channels were not found. These high threshold channels were not blocked by omega-conotoxin GVIA and were inhibited rather than activated by BAY K 8644. They were therefore pharmacologically distinct from high threshold N- and L-type channels. Funnel web spider toxin was an effective blocker. The channels opened to conductance levels of 9, 14, and 19 pS (in 110 mM Ba2+). These slope conductances were in the range of those reported for N- and L-type channels. Our results are in agreement with previous reports suggesting that Ca2+ channels in Purkinje cells can be classified as P-type channels according to their pharmacology. The results also suggest that distinctions among Ca2+ channel types based on the single-channel conductance are not definitive.

Magnetic sources of the M50 response are localized to frontal cortex.

OBJECTIVE: To determine the source localization(s) of the midlatency auditory magnetic response M50, the equivalent of the P50 potential, a sleep state-dependent waveform known to habituate to repetitive stimulation. METHODS: We used a paired stimulus paradigm at interstimulus intervals of 250, 500 and 1000 ms, and magnetoencephalographic (MEG) recordings were subjected to computational methods for current density reconstruction, blind source separation, time-frequency analysis, and data visualization to characterize evoked dynamics. RESULTS: Each subject showed localization of a source for primary auditory evoked responses in the region of the auditory cortex, usually at a 20-30 ms latency. However, responses at 40-70 ms latency that also decreased following the second stimulus of a pair were not localizable to the auditory cortex, rather showing multiple sources usually including the frontal lobes. CONCLUSIONS: The M50 response, which shows habituation to repetitive stimulation, was not localized to the auditory cortex, but showed multiple sources including frontal lobes. SIGNIFICANCE: These MEG results suggest that sources for the M50 response may represent non-auditory, perhaps arousal-related, diffuse projections to the cortex.

Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system.

In addition to the three types of voltage-dependent calcium channels presently recognized in the CNS, the L-, the T- and the N-types, a fourth distinct type known as the P-type channel has recently been described. This channel, initially recognized in Purkinje cells (and thus the name), is not blocked by dihydropyridines or by omega-conotoxin (GVIA), but is blocked by native funnel-web spider venom and by a polyamine (FTX) extracted from such venom. In addition, a synthetic polyamine (sFTX) has been produced that also specifically blocks P-channels in brain slices and at the neuromuscular junction, and blocks presynaptic Ca2+ currents in other vertebrate and invertebrate forms, as well as channels expressed in Xenopus oocytes following CNS mRNA injections. Using sFTX to form an affinity gel, a protein was isolated and reconstituted into lipid bilayers where it manifests single-channel properties that are electrophysiologically and pharmacologically similar to those of the native P-channels. Rabbits immunized with the isolated protein produced a polyclonal antibody that gave a positive western blot with the purified P-channel protein and generated a reaction product at specific sites in the CNS that agree with the physiological distribution of P-channel activity.

On the cerebellum and motor learning.

A critical review of the role of the cerebellum in motor learning is presented. Specifically, the hypothesis that the climbing fibers that issue from the inferior olive serve to modify the responsiveness of cerebellar Purkinje cells is evaluated. It is concluded that there is no convincing evidence, at this time, to support the view that a long-term modification of Purkinje cell activity is either the basis of motor learning or an authentic mechanism of cerebellar function. An alternative view, based on the biophysical, anatomical and ensemble properties of olivary neurons, suggests an important role for the olivocerebellar system in the coordination of movements. Future work in this interesting area of neuroscience will distinguish these two hypotheses.

Tau pathology-mediated presynaptic dysfunction.

Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases.

Voltage-sensitive dye imaging of neocortical spatiotemporal dynamics to afferent activation frequency.

The spatial and temporal patterns of neocortex activation are determined not only by the dynamic character of the input but also by the intrinsic dynamics of the cortical circuitry. To study the role of afferent input frequency on cortical activation dynamics, the electrical activity of in vitro neocortex slices was imaged during white-matter electrical stimulation. High-speed optical imaging was implemented using voltage-sensitive dyes in guinea pig visual and somatosensory cortex slices concomitantly with intracellular recordings. Single white-matter electrical stimuli activated well-defined cortical sites with a radially oriented columnar configuration. This configuration was followed, over the next few milliseconds, by a lateral spread of excitation through cortical layers 5 and 6 and layers 2 and 3. Much of the optical response was eliminated in low extracellular calcium, indicating that it was primarily synaptically mediated. Repetitive stimuli at 10 Hz reproduced the spatiotemporal pattern observed for single stimuli. In contrast, repetitive stimulation in the gamma frequency range ( approximately 40 Hz) rapidly restrained the area of excitation to a small columnar site directly above the stimulating electrode. Intracellular recordings from cells lateral to the activated column revealed increased inhibitory synaptic activity and/or decreased excitatory responses during the train at 40 Hz, but not during a 10 Hz stimulation. Localized microinjections of GABA(A) antagonist produced a reorganization of the geometrical activity pattern that was dependent on the position of the microinjection site. These findings indicate that the frequency-dependent spatial organization of neocortex activation is determined by inhibitory sculpting attributable to local network dynamics.