Spatiotemporal profile of synaptic activation produced by the electrical and visual stimulation of retinal inputs to the optic tectum: a current source density analysis in the pigeon (Columba livia)

The optic tectum of the pigeon is a highly organized, multilayered structure that receives a massive polystratified afference of at least five different populations of retinal ganglion cells and gives rise to various anatomically segregated efferent systems. The synaptic organization of retino-tectal circuitry is, at present, mostly unknown. To investigate the spatiotemporal profile of synaptic activation produced by differential (electrical and visual) stimulation of the retinal inputs, we performed a high-spatial-resolution current source density analysis in the optic tectum of the anaesthetized pigeon. Electrical stimuli consisted of brief pulses of different durations applied to the optic nerve head, while visual stimuli consisted of light flashes of different intensities. Electrical stimulation generated sinks confined to retinorecipient layers. The temporal structure, spatial location and thresholds of these sinks indicated that they are all due to primary tectal synapses of retinal fibers with different conduction velocities. Sinks evoked by the fastest retinal axons were more superficially located than sinks produced by slower retinal fibers. Visual stimulation, on the other hand, resulted in a more complex pattern of current sinks, with various sinks located in the retinorecipient layers and also well below. Visual stimulation induced action potentials at superficial as well as deep tectal levels. We conclude that electrical stimulation activates most of the populations of ganglion cells as well as their primary tectal synapses, but is unable to elicit a significant activation of secondary tectal synapses. Visual stimulation, on the contrary, activates just some of the incoming retinal populations, but in a way that produces noticeable secondary activation of intratectal circuits. Laminar segregation of retinally evoked tectal activity, as reported here, has also been found in other vertebrates. Similarities and differences with previous studies are discussed.     

Generator localization by current source density (CSD): Implications of volume conduction and field closure at intracranial and scalp resolutions

The topographic ambiguity and reference-dependency that has plagued EEG/ERP research throughout its history are largely attributable to volume conduction, which may be concisely described by a vector form of Ohm’s Law. This biophysical relationship is common to popular algorithms that infer neuronal generators via inverse solutions. It may be further simplified as Poisson’s source equation, which identifies underlying current generators from estimates of the second spatial derivative of the field potential (Laplacian transformation). Intracranial current source density (CSD) studies have dissected the “cortical dipole” into intracortical sources and sinks, corresponding to physiologically-meaningful patterns of neuronal activity at a sublaminar resolution, much of which is locally cancelled (i.e., closed field). By virtue of the macroscopic scale of the scalp-recorded EEG, a surface Laplacian reflects the radial projections of these underlying currents, representing a unique, unambiguous measure of neuronal activity at scalp. Although the surface Laplacian requires minimal assumptions compared to complex, model-sensitive inverses, the resulting waveform topographies faithfully summarize and simplify essential constraints that must be placed on putative generators of a scalp potential topography, even if they arise from deep or partially-closed fields. CSD methods thereby provide a global empirical and biophysical context for generator localization, spanning scales from intracortical to scalp recordings.     

Frontal theta and posterior alpha in resting EEG: A critical examination of convergent and discriminant validity

Prior research has identified two resting EEG biomarkers with potential for predicting functional outcomes in depression: theta current density in frontal brain regions (especially rostral anterior cingulate cortex) and alpha power over posterior scalp regions. As little is known about the discriminant and convergent validity of these putative biomarkers, a thorough evaluation of these psychometric properties was conducted toward the goal of improving clinical utility of these markers. Resting 71-channel EEG recorded from 35 healthy adults at two sessions (1-week retest) were used to systematically compare different quantification techniques for theta and alpha sources at scalp (surface Laplacian or current source density [CSD]) and brain (distributed inverse; exact low resolution electromagnetic tomography [eLORETA]) level. Signal quality was evaluated with signal-to-noise ratio, participant-level spectra, and frequency PCA covariance decomposition. Convergent and discriminant validity were assessed within a multitrait-multimethod framework. Posterior alpha was reliably identified as two spectral components, each with unique spatial patterns and condition effects (eyes open/closed), high signal quality, and good convergent and discriminant validity. In contrast, frontal theta was characterized by one low-variance component, low signal quality, lack of a distinct spectral peak, and mixed validity. Correlations between candidate biomarkers suggest that posterior alpha components constitute reliable, convergent, and discriminant biometrics in healthy adults. Component-based identification of spectral activity (CSD/eLORETA-fPCA) was superior to fixed, a priori frequency bands. Improved quantification and conceptualization of frontal theta is necessary to determine clinical utility.     

Stable dry powder inhaler formulation of tranilast attenuated antigen-evoked airway inflammation in rats

Tranilast (TL) has been clinically used for the treatment of airway inflammatory diseases, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder of TL (CSD/TL-RP) for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). Stability study on CSD/TL-RP was carried out with a focus on inhalation performance. Even after 6 months of storage at room temperature, there were no significant morphological changes in micronized particles on the surface of carrier particles as compared with that before storage. Cascade impactor analyses on CSD/TL-RP demonstrated high inhalation performance with emitted dose and fine particle fraction (FPF) of ca. 98% and 60%, respectively. Long-term storage of CSD/TL-RP resulted in only a slight decrease in FPF value (ca. 54%). Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by marked reduction of granulocytes in bronchoalveolar lavage fluid and inflammatory biomarkers such as eosinophil peroxidase, myeloperoxidase, and lactate dehydrogenase. These findings were consistent with decreased expression levels of mRNAs for nuclear factor-kappa B and cyclooxygenase-2, typical inflammatory mediators. Given these findings, inhalable TL formulation might be an interesting alternative to oral therapy for the treatment of asthma and other airway inflammatory diseases with sufficient dispersing stability.     

Targeting KIT in melanoma: A paradigm of molecular medicine and targeted therapeutics

Despite multiple clinical trials utilizing a spectrum of therapeutic modalities, melanoma remains a disease with dismal outcomes in patients with advanced disease. However, it is now clear that melanoma is not a single entity, but can be molecularly divided into subtypes that generally correspond to the anatomical location of the primary melanoma. Melanomas from acral lentiginous, mucosal, and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in the more common cutaneous tumors. Multiple case reports and early observations from clinical trials suggest that targeting mutant KIT with tyrosine kinase inhibitors is efficacious in KIT mutant melanoma. This review recounts what is known about the role of KIT in melanocyte maturation, our current understanding of KIT genetic aberrations in melanoma, and how this knowledge is being translated into clinical oncology.     

Effects of acute and chronic anti-panic drug administration on conflict behavior in the rat

The present studies were undertaken to evaluate further the utility of the Conditioned Suppression of Drinking (CSD) conflict pardigm as an animal model for the study of panic disorder and anti-panic agents. In daily 10-min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA). Electrification was signalled by a tone. Desipramine (DMI), amitriptyline (AMI), or phenelzine (PHEN) was administered both in acute (10-min pre-treatment) and chronic (twice daily for up to 9 weeks) regimens. Acute administration of DMI, AMI or PHEN over a wide range of doses resulted in no change or a decrease in the number of shocks accepted and a decrease in water intake at higher doses. In contrast, chronic administration of each agent resulted in a gradual (2–4 week latency) increase in the number of shocks received in CSD sessions over the course of several weeks of testing. This time-dependent increase in punished responding in the CSD observed during chronic anti-panic drug treatment parallels the time-dependent reduction in the severity and frequency of panic attacks in panic disorder patients receiving chronic antidepressants. Thus, the CSD paradigm might serve as an animal model for the study of panic disorder and potential anti-panic agents.     

Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes

The insulin receptor-independent insulin-mimetic signalling provoked by the antidiabetic sulfonylurea drug, glimepiride, is accompanied by the redistribution and concomitant activation of lipid raft-associated signalling components, such as the acylated tyrosine kinase, pp59(Lyn), and some glycosylphosphatidylinositol-anchored proteins (GPI-proteins). We now found that impairment of glimepiride-induced lipolytic cleavage of GPI-proteins in rat adipocytes by the novel inhibitor of glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), GPI-2350, caused almost complete blockade of (i) dissociation from caveolin-1 of pp59(Lyn) and GPI-proteins, (ii) their redistribution from high cholesterol- (hcDIGs) to low cholesterol-containing (lcDIGs) lipid rafts, (iii) tyrosine phosphorylation of pp59(Lyn) and insulin receptor substrate-1 protein (IRS-1) and (iv) stimulation of glucose transport as well as (v) inhibition of isoproterenol-induced lipolysis in response to glimepiride. In contrast, blockade of the moderate insulin activation of the GPI-PLC and of lipid raft protein redistribution by GPI-2350 slightly reduced insulin signalling and metabolic action, only. Importantly, in response to both insulin and glimepiride, lipolytically cleaved hydrophilic GPI-proteins remain associated with hcDIGs rather than redistribute to lcDIGs as do their uncleaved amphiphilic versions. In conclusion, GPI-PLC controls the localization within lipid rafts and thereby the activity of certain GPI-anchored and acylated signalling proteins. Its stimulation is required and may even be sufficient for insulin-mimetic cross-talking to IRS-1 in response to glimepiride via redistributed and activated pp59(Lyn).     

Retino-hypothalamic-pineal hypothesis in the pathophysiology of primary headaches

Primary headaches include migraine, tension, cluster headaches, paroxysmal hemicrania and miscellaneous headaches unassociated with structural lesions. A putative role of the retino-hypothalamic-pineal (RHP) axis in the pathophysiology of primary headaches is reviewed in terms of (1) retinal dysfunction, (2) hypothalamic dysfunction and human circadian desynchrony, (3) pineal melatonin dysfunction and (4) rostral limbic dysfunction mediating the human stress response. Unified RHP hypothesis is proposed, suggesting that an acute, periodic or chronic, circadian desynchrony and dysfunction of the whole or part of the RHP axis is implicated in the pathophysiology of primary headaches. Supportive evidence for the RHP hypothesis, including recent PET studies showing changes in dorsal pons, hypothalamus and rostral limbic structures, is presented.