Damage to the adult, primary visual cortex (V1) causes severe visual impairment that was previously thought to be permanent, yet several visual pathways survive V1 damage, mediating residual, often unconscious functions known as "blindsight." Because some of these pathways normally mediate complex visual motion perception, we asked whether specific training in the blind field could improve not just simple but also complex visual motion discriminations in humans with long-standing V1 damage. Global direction discrimination training was administered to the blind field of five adults with unilateral cortical blindness. Training returned direction integration thresholds to normal at the trained locations. Although retinotopically localized to trained locations, training effects transferred to multiple stimulus and task conditions, improving the detection of luminance increments, contrast sensitivity for drifting gratings, and the extraction of motion signal from noise. Thus, perceptual relearning of complex visual motion processing is possible without an intact V1 but only when specific training is administered in the blind field. These findings indicate a much greater capacity for adult visual plasticity after V1 damage than previously thought. Most likely, basic mechanisms of visual learning must operate quite effectively in extrastriate visual cortex, providing new hope and direction for the development of principled rehabilitation strategies to treat visual deficits resulting from permanent visual cortical damage.

Damage to the primary visual cortex (V1) or its immediate afferents results in a dense scotoma, termed cortical blindness (CB). CB subjects have residual visual abilities, or blindsight, which allow them to detect and sometimes discriminate stimuli with high temporal and low spatial frequency content. Recent work showed that with training, discriminations in the blind field can become more reliable, and even reach consciousness. However, the narrow spatiotemporal bandwidth of blindsight limits its functional usefulness in everyday vision. Here, we asked whether visual training can induce recovery outside the spatiotemporal bandwidth of blindsight. Specifically, could human CB subjects learn to discriminate static, nonflickering stimuli? Can such learning transfer to untrained stimuli and tasks, and does double training with moving and static stimuli provide additional advantages relative to static training alone? We found CB subjects capable of relearning static orientation discriminations following single as well as double training. However, double training with complex, moving stimuli in a separate location was necessary to recover complex motion thresholds at locations trained with static stimuli. Subjects trained on static stimuli alone could only discriminate simple motion. Finally, both groups had approximately equivalent, incomplete recovery of fine orientation and direction discrimination thresholds, as well as contrast sensitivity. These results support two conclusions: (1) from a practical perspective, complex moving stimuli and double training may be superior training tools for inducing visual recovery in CB, and (2) the cortically blind visual system can relearn to perform a wider range of visual discriminations than predicted by blindsight alone.

Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-b is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator-activated receptor (PPAR) g is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARg ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-b-stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of a-smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARg ligand, 15-deoxy-D 12,14 -prostaglandin J 2 (15 d-PGJ 2 ), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARg-independent pathway. CDDO and 15 d-PGJ 2 contain an a/b unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A 1 and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ 2 lacking the electrophilic center is much less potent. CDDO does not alter TGF-b-induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-b-responsive genes. Overall, these data indicate that certain PPARg ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-b-mediated profibrogenic activities through pathways independent of PPARg. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high.

Objective:To assess if visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement.Methods:24-2 and 10-2 Humphrey visual fields were analyzed for 17 chronic cortically blind stroke patients prior to and following visual discrimination training, as well as in 5 untrained, cortically blind controls. Trained patients practiced direction discrimination, orientation discrimination, or both, at nonoverlapping, blind field locations. All pretraining and posttraining discrimination performance and Humphrey fields were collected with online eye tracking, ensuring gaze-contingent stimulus presentation.Results:Trained patients recovered ∼108 degrees2 of vision on average, while untrained patients spontaneously improved over an area of ∼16 degrees2. Improvement was not affected by patient age, time since lesion, size of initial deficit, or training type, but was proportional to the amount of training performed. Untrained patients counterbalanced their improvements with worsening of sensitivity over ∼9 degrees2 of their visual field. Worsening was minimal in trained patients. Finally, although discrimination performance improved at all trained locations, changes in Humphrey sensitivity occurred both within trained regions and beyond, extending over a larger area along the blind field border.Conclusions:In adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field. Our findings underscore a critical need for future studies to measure the effects of vision restoration approaches on perimetry in larger cohorts of patients.