Estimation of Mental Effort in Learning Visual Search by Measuring Pupil Response

Perceptual learning refers to the improvement of perceptual sensitivity and performance with training. In this study, we examined whether learning is accompanied by a release from mental effort on the task, leading to automatization of the learned task. For this purpose, we had subjects conduct a visual search for a target, defined by a combination of orientation and spatial frequency, while we monitored their pupil size. It is well known that pupil size reflects the strength of mental effort invested in a task. We found that pupil size increased rapidly as the learning proceeded in the early phase of training and decreased at the later phase to a level half of its maximum value. This result does not support the simple automatization hypothesis. Instead, it suggests that the mental effort and behavioral performance reflect different aspects of perceptual learning. Further, mental effort would be continued to be invested to maintain good performance at a later stage of training

Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles

Encapsulation of therapeutic molecules within polymer particles is a well-established method for achieving controlled release, yet challenges such as low loading, poor encapsulation efficiency, and loss of protein activity limit clinical translation. Despite this, the paradigm for the use of polymer particles in drug delivery has remained essentially unchanged for several decades. By taking advantage of the adsorption of protein therapeutics to poly(lactic-co-glycolic acid) (PLGA) nanoparticles, we demonstrate controlled release without encapsulation. In fact, we obtain identical, burst-free, extended-release profiles for three different protein therapeutics with and without encapsulation in PLGA nanoparticles embedded within a hydrogel. Using both positively and negatively charged proteins, we show that short-range electrostatic interactions between the proteins and the PLGA nanoparticles are the underlying mechanism for controlled release. Moreover, we demonstrate tunable release by modifying nanoparticle concentration, nanoparticle size, or environmental pH. These new insights obviate the need for encapsulation and offer promising, translatable strategies for a more effective delivery of therapeutic biomolecules

Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair

In the adult brain, endogenous neural stem and progenitor cells (NSPCs) can be stimulated to promote tissue and functional repair after traumatic injury, such as stroke. Cyclosporine (CsA) stimulates endogenous neural stem cells and erythropoietin (EPO) promotes neurogenesis, making their dual delivery compelling for investigation. However, the blood brain barrier poses a significant challenge for drug-based neural repair strategies. To overcome this barrier, a minimally invasive polymer system was developed for local drug delivery to the brain. The polymer system is composed of a hyaluronan and methylcellulose (HAMC) hydrogel depot carrying drug-loaded poly(lactic-co-glycolic) acid microparticles. The hydrogel depot was delivered epi-cortically, onto the surface of the brain, in a rat model of transient ischemic stroke. Local delivery with the polymer system was compared to systemic delivery using osmotic minipumps, with CsA serving as a model compound. With local delivery, higher tissue concentrations of CsA were achieved in the brain and significantly reduced concentrations were observed in non-targeted organs, compared to systemic delivery. The system was expanded to co-release CsA and EPO and the effects on post-stroke motor recovery and chronic tissue repair were evaluated. Both drugs were released for 4 weeks post-implantation and diffused to the sub-cortical NSPC niche located along the lateral walls of the ventricles. Only co-delivery of CsA and EPO (relative to all other controls, including delivery of each drug alone) increased and accelerated recovery in two different forelimb motor tasks: cylinder and staircase. Differential effects of the two drugs were seen on NSPC stimulation and synaptic plasticity: EPO increased the number of NSPCs found in the ventricles while CsA increased the number of proliferating NSPCs and synaptic plasticity in the striatum. Only the combination of CsA and EPO decreased the stroke lesion volume. Combined, this work demonstrates that local drug delivery with the polymer system can stimulate endogenous brain repair. This approach is amenable to a wide range of drugs that can target different aspects of tissue repair and can be combined with other reparative approaches, such as cell delivery or rehabilitation therapy, to enhance recovery after stroke. Στον ενήλικο εγκέφαλο, ενδογενή νευρικά βλαστοκύτταρα και προγονικά κύτταρα (NSPCs) μπορούν να διεγερθούν για να προωθήσουν ιστούς και λειτουργική αποκατάσταση μετά από τραυματικές βλάβες, όπως εγκεφαλικό επεισόδιο. Η κυκλοσπορίνη (CsA) διεγείρει τα ενδογενή νευρικά βλαστικά κύτταρα και η ερυθροποιητίνη (ΕΡΟ) προάγει τη νευρογένεση, καθιστώντας τη διπλή απεικόνισή τους επιτακτική για τη διερεύνηση. Ωστόσο, το φράγμα αίματος εγκεφάλου αποτελεί σημαντική πρόκληση για τις στρατηγικές νευρικής αποκατάστασης που βασίζονται σε φάρμακα. Για να ξεπεραστεί αυτός ο φραγμός, αναπτύχθηκε ένα ελάχιστα επεμβατικό σύστημα πολυμερούς για την τοπική χορήγηση φαρμάκου στον εγκέφαλο. Το σύστημα πολυμερούς αποτελείται από ένα υδραυλικό πήκτωμα υαλουρονάνης και μεθυλοκυτταρίνης (HAMC) που φέρει μικροσωματίδια πολυ (γαλακτικό-συν-γλυκολικό) οξύ φορτισμένο με φάρμακο. Η αποθήκη υδρογέλης απελευθερώθηκε επιδερμικώς, επάνω στην επιφάνεια του εγκεφάλου, σε μοντέλο αρουραίου παροδικού ισχαιμικού αγγειακού εγκεφαλικού επεισοδίου. Η τοπική απελευθέρωση με το πολυμερές σύστημα συγκρίθηκε με συστηματική χορήγηση με χρήση οσμωτικών μίνι αντλιών, με CsA να χρησιμεύει ως ένωση μοντέλου. Με την τοπική χορήγηση, υψηλότερες συγκεντρώσεις ιστού CsA επιτεύχθηκαν στον εγκέφαλο και παρατηρήθηκαν σημαντικά μειωμένες συγκεντρώσεις σε μη στοχευμένα όργανα, σε σύγκριση με συστηματική χορήγηση. Το σύστημα επεκτάθηκε για να συν-απελευθερώσει CsA και ΕΡΟ και αξιολογήθηκαν οι επιδράσεις στην αποκατάσταση μετά από εγκεφαλικό επεισόδιο κινητήρα και χρόνια αποκατάσταση ιστού. Και τα δύο φάρμακα απελευθερώθηκαν για 4 εβδομάδες μετά την εμφύτευση και διαχέονται στην υποφλοιώδη θέση NSPC που βρίσκεται κατά μήκος των πλευρικών τοιχωμάτων των κοιλιών. Μόνο η παράδοση των CsA και EPO (σε σχέση με όλους τους άλλους ελέγχους, συμπεριλαμβανομένης της παράδοσης κάθε φαρμάκου και μόνο) αύξησε και επιτάχυνε την ανάκτηση σε δύο διαφορετικά καθήκοντα του κινητήρα: κύλινδρο και σκάλα. Διαφορετικές επιδράσεις των δύο φαρμάκων παρατηρήθηκαν σε διέγερση NSPC και συνοπτική πλαστικότητα: Η ΕΡΟ αύξησε τον αριθμό των NSPCs που βρέθηκαν στις κοιλίες ενώ η CsA αύξησε τον αριθμό των πολλαπλασιαστικών NSPCs και της συναπτικής πλαστικότητας στο ραβδωτό σώμα. Μόνο ο συνδυασμός CsA και ΕΡΟ μείωσε τον όγκο της βλάβης του εγκεφαλικού. Σε συνδυασμό, αυτή η εργασία καταδεικνύει ότι η τοπική χορήγηση φαρμάκου με το πολυμερές σύστημα μπορεί να διεγείρει την ενδογενή επισκευή του εγκεφάλου. Αυτή η προσέγγιση είναι επιδεκτική σε ένα ευρύ φάσμα φαρμάκων που μπορούν να στοχεύουν διαφορετικές πτυχές της επισκευής ιστών και μπορούν να συνδυαστούν με άλλες προσεγγίσεις αποκατάστασης, όπως η χορήγηση κυττάρων ή η θεραπεία αποκατάστασης, για την ενίσχυση της ανάρρωσης μετά από εγκεφαλικό επεισόδιο.Ph.D

Simulating progressive neurodegeneration in silico with deep artificial neural networks

We recently proposed a novel paradigm of using convolutional neural networks (CNNs) to model information processing in the diseased brain. Previously, we simulated posterior cortical atrophy (PCA), a form of Alzheimer’s disease primarily impacting the visual cortex and manifesting as visual cognition deficits, by ablating CNN weights. However, this approach modelled a synaptic ablation injury, which resulted in the rapid onset of functional impairments. Here, we investigate using a weight decay function to simulate a gradual synaptic injury. In contrast to ablation injury, the onset of functional deficits was slower with the proposed weight decay injury. If only a subset of the network weights were subject to a decay injury, the delayed onset of functional deficits was even more pronounced. This approach may better reflect the subtle atrophy that precedes symptoms and the gradual onset of functional impairments seen in patients with neurodegenerative diseases such as PCA and Alzheimer’s disease

Normalized average pupil diameter as a function of the training day.

<p>Filled squares denote the averaged pupil diameter of 12 subjects conducting the visual conjunction search task. In the passive condition (blank triangles), subjects observed the same display but no task was imposed. The data was calculated from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0021973#pone-0021973-g003" target="_blank">Fig. 3</a>. Error bars represent ±1SEM.</p

Normalized pupil diameter as a function of time.

<p>(A) Each function represents the averaged pupil diameter of 12 subjects during the conduction of the visual conjunction search task. The data in each trial was normalized relative to the pupil size during the cross fixation period immediately preceding the trial. Different functions denote the different training day: 1^st, 3^rd, 5^th, and 10^th day, respectively. (B) Each function represents the averaged pupil diameter of 12 subjects conducting the passive viewing task. In passive condition subjects observed the visual search display, but no task was imposed. The data in each trial was normalized relative to the pupil size during the cross fixation period immediately preceding the trial. Different functions denote the different experimental day: 1^st, 3^rd, 5^th, and 10^th day, respectively.</p

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

Stroke is a devastating disease for which no clinical treatment exists to regenerate lost tissue. Strategies for brain repair in animal models of stroke include the delivery of drug or cell-based therapeutics; however, the complex anatomy and functional organization of the brain presents many challenges. Biomaterials may alleviate some of these challenges by providing a scaffold, localizing the therapy to the site of action, and/or modulating cues to brain cells. Here, the challenges associated with delivery of therapeutics to the brain and the biomaterial strategies used to overcome these challenges are described. For example, innovative hydrogel delivery systems have been designed to provide sustained trophic factor delivery for endogenous repair and to support transplanted cell survival and integration. Novel treatments, such as electrical stimulation of transplanted cells and the delivery of factors for the direct reprogramming of astrocytes into neurons, may be further enhanced by biomaterial delivery systems. Ultimately, improved clinical translation will be achieved by combining clinically relevant therapies with biomaterials strategies

Normalized pupil diameter 1 second after the onset of the visual search display.

<p>Filled squares denote the averaged pupil diameter of 12 subjects 1 second after the onset of the visual search display, as a function of the training day. The data was calculated from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0021973#pone-0021973-g003" target="_blank">Fig. 3(A)</a>. Error bars represent ±1SEM.</p

Learning curve of the conjunction search task.

<p>Reaction time in seconds as a function of training day is plotted. Filled red squares denote the data when the target is presented. Blank blue squares denote when the target is absent. The data from 12 subjects are averaged. Error bars represent ±1SEM.</p