Vision loss in glaucoma is caused by progressive dysfunction of retinal ganglion cells (RGCs) and optic nerve atrophy. Here, we investigated the effectiveness of BDNF treatment to preserve vision in a glaucoma experimental model. As an established experimental model, we used the DBA/2J mouse, which develops chronic intraocular pressure (IOP) elevation that mimics primary open-angle glaucoma (POAG). IOP was measured at different ages in DBA/2J mice. Visual function was monitored using the steady-state Pattern Electroretinogram (P-ERG) and visual cortical evoked potentials (VEP). RGC alterations were assessed using Brn3 immunolabeling, and confocal microscope analysis. Human recombinant BDNF was dissolved in physiological solution (0.9% NaCl); the effects of repeated intravitreal injections and topical eye BDNF applications were independently evaluated in DBA/2J mice with ocular hypertension. BDNF level was measured in retinal homogenate by ELISA and western blot. We found a progressive decline of P-ERG and VEP responses in DBA/2J mice between 4 and 7 months of age, in relationship with the development of ocular hypertension and the reduction of Brn3 immunopositive RGCs. Conversely, repeated intravitreal injections (BDNF concentration = 2 µg/µl, volume = 1 µl, for each injection; 1 injection every four days, three injections over two weeks) and topical eye application of BDNF eye-drops (12 µg/µl, 5 µl eye-drop every 48 h for two weeks) were able to rescue visual responses in 7 month DBA/2J mice. In particular, BDNF topical eye treatment recovered P-ERG and VEP impairment increasing the number of Brn3 immunopositive RGCs. We showed that BDNF effects were independent of IOP reduction. Thus, topical eye treatment with BDNF represents a promisingly safe and feasible strategy to preserve visual function and diminish RGC vulnerability to ocular hypertension.
In the general population, transcranial anodal direct current stimulation of the cerebellum (ctDCS) reduces pain intensity and the amplitude of nociceptive laser evoked potentials (LEPs), whereas cathodal ctDCS elicits opposite effects. Since behavioral findings suggest that the cerebellar activity of highly hypnotizable individuals (highs) differs from the general population, we investigated whether hypnotizability-related differences occur in the modulation of pain by ctDCS. Sixteen healthy highs (according to the Stanford Hypnotic Susceptibility Scale, form A) and 16 participants not selected according to hypnotizability (controls) volunteered to undergo laser nociceptive stimulation of the dorsum of the left hand before and after anodal or cathodal ctDCS. LEPs amplitudes and latencies and the subjective pain experience (Numerical Rating Scale) were analyzed. Smaller LEP amplitudes and longer latencies were observed in highs with respect to controls independently of stimulation. After anodal and cathodal cerebellar stimulation, controls reported lower and higher pain than before it, respectively. In contrast, highs did not report significant changes in the perceived pain after both stimulations. They increased significantly their N2/P2 amplitude after anodal ctDCS and did not exhibit any significant change after cathodal tDCS, whereas controls decreased the N1 and N2P2 amplitude and increased their latency after anodal cerebellar stimulation and did the opposite after cathodal ctDCS. In conclusion, the study showed impaired cerebellar pain modulation and suggested altered cerebral cortical representation of pain in subjects with high hypnotizability scores.
Event-Related Potentials (ERPs) occurring independently from any stimulus are purely endogenous ( emitted potentials ) and their neural generators can be unequivocally linked with cognitive processes. In the present study, the subjects performed two similar visual counting tasks: a standard two-stimulus oddball, and an omitted-target oddball task, characterized by the physical absence of the target stimulus. Our investigation aimed at localizing the neural sources of the scalp-recorded endogenous/emitted ERPs. To optimize the source localization, the high temporal resolution of electrophysiology was combined with the fine spatial information provided by the simultaneous recording of functional magnetic resonance (fMRI). Both tasks identified two endogenous ERP components in the 300 to 520 ms interval. An earlier component, pP2, showed a bilateral generator in the anterior Insula. A later P3 component (P3b) was generated bilaterally in the temporal-parietal junction, the premotor and motor area and the anterior intraparietal sulcus (this latter one only in the standard oddball). Anticipatory slow waves (beginning 900 to 500 ms pre-stimulus), also of endogenous nature, were produced by the inferior and middle frontal gyrus and the supplementary and cingulate motor areas. Our protocol disentangled pre- from post-stimulus fMRI activations and provided original clues to the psychophysiological interpretation of emitted/endogenous ERPs.
The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the ‘staircase’ method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as ‘juvenile’, ‘mature’ and ‘elder’. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes.
Purpose: To test whether the topical eye treatment with BDNF prevents the effects of continuous light exposure (LE) in the albino rat retina.Methods: Two groups of albino rats were used. The first group of rats received an intraocular injection of BDNF (2 lL, 1 lg/lL) before LE, while the second group was treated with one single drop of BDNF (10 lL, 12 lg/lL) dissolved in different types of solutions (physiological solution, the polysaccharide fraction of Tamarind gum, TSP, and sodium carboxy methyl cellulose), at the level of conjunctival fornix before LE. The level of BDNF in the retina and optic nerve was determined by enzyme-linked immunosorbent assay. We recorded the flash electroretinogram (fERG) in dark adapted rats 1 week after LE. At the end of the recording session, the retinas were removed and labeled so that the number of photoreceptors nuclear rows and thickness of the outer nuclear layer was analyzed.Results: Intravitreal injection of BDNF before LE prevented fERG impairment. Different ophthalmic preparations were used for topical eye application; the TSP resulted the most suitable vehicle to increase BDNF level in the retina and optic nerve. Topical eye application with BDNF/TSP before LE partially preserved both fERG response and photoreceptors.Conclusions: Topical eye treatment with BDNF represents a suitable, noninvasive tool to increase the retinal content of BDNF up to a level capable of exerting neuroprotection toward photoreceptors injured by prolonged LE.Translational Relevance: A collyrium containing BDNF may serve as an effective, clinically translational treatment against retinal degeneration.
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