Decreased activity of piriform cortex and orbitofrontal hyperactivation in Usher Syndrome, a human disorder of ciliary dysfunction.

Usher syndrome (USH) is a condition characterized by ciliary dysfunction leading to retinal degeneration and hearing/vestibular loss. Putative olfactory deficits in humans have been documented at the psychophysical level and remain to be proven at the neurophysiological level. Thus, we aimed to study USH olfactory impairment using functional magnetic resonance imaging. We analyzed differences in whole-brain responses between 27 USH patients and 26 healthy participants during an olfactory detection task with a bimodal odorant (n-butanol). The main research question was whether between-group differences could be identified using a conservative whole-brain approach and in a ROI-based approach in key olfactory brain regions. Results indicated higher olfactory thresholds in USH patients, thereby confirming the hypothesis of reduced olfactory acuity. Importantly, we found decreased BOLD activity for USH patients in response to odorant stimulation in the right piriform cortex, while right orbitofrontal cortex showed increased activity. We also found decreased activity in other higher-level regions in a whole brain approach. We suggest that the hyper activation in the orbitofrontal cortex possibly occurs as a compensatory mechanism after the under-recruitment of the piriform cortex. This study suggests that olfactory deficits in USH can be objectively assessed using functional neuroimaging which reveals differential patterns of activity both in low- and high-level regions of the olfactory network.

Prediction and cost-effectiveness comparison of amblyopia screening methods at ages 3-4 years.

PURPOSE: Compare the performance of different amblyopia screening tests. METHODS: Based on exploratory factor analyses (EFA) of different screening tests performed in 3295 children, we created models of screening strategies in a matrix with: uncorrected visual acuity (UCVA), Plusoptix measurements (PO), Randot Stereo-test (SR), and Cover-Test (CT). Receiver Operating Characteristic (ROC) curves and confusion matrix were used to compare performance of different model's algorithm to predict new diagnosis of amblyopia. Estimated screening costs per screened and treated child were compared. RESULTS: Regression analyses revealed that, although all models predicted amblyopia (all p < 0.001), only models including PO or UCVA had higher prediction capacity (R2 > 0.4) and better discriminating ROC curves (AUC > 0.95; p < 0.001). For 96% sensitivity, UCVA + PO was the most cost-effective model, since the estimated average screening costs per treated child, almost doubled and tripled if using PO or UCVA alone, respectively, versus using both exams. When UCVA + PO is not possible to implement, adding SR to either UCVA or PO resulted in cost-savings of 28% and 18%, respectively. CONCLUSIONS: In a previous unscreened population, aged 3-4 years, screening programs using either UCVA or PO alone, should reconsider doing both tests simultaneously, since, for a high level of sensitivity, using simultaneously UCVA + PO is more cost-effective, per screened, and treated amblyopia. Concerns relating higher time-consuming exams for the combination of UCVA + PO should be surpassed, since costs per treated child drop considerably. When children benefit from good primary-care routine examinations since birth, no benefit was found for using CT in a screening setting. SR showed little benefit.

Enhanced Visual Attentional Modulation in Patients with Inherited Peripheral Retinal Degeneration in the Absence of Cortical Degeneration.

The role of attentional mechanisms in peripheral vision loss remains an outstanding question. Our study was aimed at determining the effect of genetically determined peripheral retinal dystrophy caused by Retinitis Pigmentosa (RP) on visual cortical function and tested the recruitment of attentional mechanisms using functional magnetic resonance imaging (fMRI). We included thirteen patients and twenty-two age- and gender-matched controls. We analyzed cortical responses under attentional demands and passive viewing conditions while presenting a visual stimulus covering the central and paracentral visual field. Brain activity was studied in visual areas V1, V2, and V3 as well as in cortical regions of interest corresponding to the preserved and the damaged visual field. The influence of visual field extent and age of disease onset were also investigated. Cortical thickness of visual areas was also measured. We found that cortical visual responses under attentional demands were increased in patients with larger degeneration of visual field, as demonstrated by significant interaction effects between group and task conditions. Moreover, activation during the task condition was increased for patients in two cortical regions of interest corresponding to the preserved and damaged visual field, specifically in patients with severe visual field loss. These findings were observed in the presence of preserved visual cortical structure. We conclude that RP patients have enhanced visual attention recruitment despite their retinal degeneration, while cortical structure and overall response levels remain intact. The unmasking of feedback signals from higher level visual regions involved in attentional processes may explain the increased cortical responses. These findings are relevant for the design of strategies for treating retinal diseases, based on attentional cuing.

Primary visual cortical remapping in patients with inherited peripheral retinal degeneration.

Human studies addressing the long-term effects of peripheral retinal degeneration on visual cortical function and structure are scarce. Here we investigated this question in patients with Retinitis Pigmentosa (RP), a genetic condition leading to peripheral visual degeneration. We acquired functional and anatomical magnetic resonance data from thirteen patients with different levels of visual loss and twenty-two healthy participants to study primary (V1) visual cortical retinotopic remapping and cortical thickness. We identified systematic visual field remapping in the absence of structural changes in the primary visual cortex of RP patients. Remapping consisted in a retinotopic eccentricity shift of central retinal inputs to more peripheral locations in V1. Importantly, this was associated with changes in visual experience, as assessed by the extent of the visual loss, with more constricted visual fields resulting in larger remapping. This pattern of remapping is consistent with expansion or shifting of neuronal receptive fields into the cortical regions with reduced retinal input. These data provide evidence for functional changes in V1 that are dependent on the magnitude of peripheral visual loss in RP, which may be explained by rapid cortical adaptation mechanisms or long-term cortical reorganization. This study highlights the importance of analyzing the retinal determinants of brain functional and structural alterations for future visual restoration approaches.

Risk of multiple sclerosis after optic neuritis in patients with normal baseline brain MRI.

When assessing and managing a patient with optic neuritis (ON), the risk of future development of multiple sclerosis (MS) is an important issue, as this can be the first presentation of the disease. Although the presence of lesions on baseline brain MRI is the strongest predictor of MS conversion, some patients with normal imaging also develop MS. We aimed to estimate MS risk in patients with ON and a normal baseline MRI and identify individuals with higher risk of conversion. We performed a retrospective study including patients with idiopathic ON and normal baseline brain MRI who presented to our hospital over an 8 year period. Of a total of 42 patients, 10 converted to MS: five during the first follow-up year, seven during the first 2 years and all of the patients within the first 5 years, with a 5 year MS conversion rate of 23.8%. MS conversion rates were significantly higher in patients with history of previous symptoms suggestive of demyelination (p=0.002), cerebrospinal fluid oligoclonal bands unmatched in serum (p=0.004) and incomplete visual acuity recovery (≤6/12) after 1 year (p=0.002). Lower conversion rates were found in patients with optic disc edema (p=0.022). According to these results, a significant proportion of patients with idiopathic ON and a normal baseline brain MRI will develop MS, with a higher risk during the first 5 years. Therefore, in the presence of factors in favor of MS conversion, close follow-up, including semestral medical consultations and yearly brain MRI, can be recommended. Early immunomodulatory treatment may be individually considered as it can delay conversion and reduce new lesion development rate.

Abnormal achromatic and chromatic contrast sensitivity in neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is a monogenic disorder with the majority of patients presenting subtle to moderate cognitive impairments. Visuospatial deficits are considered to be one of the hallmark characteristics of their cognitive profile. However, low-level visual processing has not been previously investigated. Our aim was to study contrast perception in these patients to assess the function of early visual areas. METHODS: Contrast sensitivity was tested in 19 children and adolescents with NF1 and 33 control children and adolescents and 12 adults with NF1 and 24 control adults. The tasks used probed two achromatic spatiotemporal frequency channels and chromatic red-green and blue-yellow pathways. RESULTS: Individuals with NF1 showed significant contrast sensitivity deficits for the achromatic higher spatial frequency channel [F(1,83) = 36.1, P < 0.001] and for the achromatic low spatial high temporal (magnocellular) frequency channel [F(1,72) = 8.0, P < 0.01]. Furthermore, individuals with NF1 presented a significant deficit in chromatic red-green (parvocellular) contrast sensitivity (P < 0.01) but not in blue-yellow (koniocelular) sensitivity. The decrease in achromatic sensitivity for higher spatial frequency was observed throughout the visual field, in both central and peripheral locations. In contrast, central contrast sensitivity for the magnocellular-biased condition was relatively preserved and only peripheral sensitivity was affected. Interestingly, the same pattern of deficits was found in both age groups tested. CONCLUSIONS: These findings showed that contrast sensitivity is impaired in patients with NF1, associating for the first time abnormal low-level vision to the cognitive profile of this disorder.

ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis.

PURPOSE: To resolve the spectrum of causative retina-specific ATP-binding cassette transporter gene (ABCA4) gene mutations in Portuguese Stargardt (STGD) patients and compare allele frequencies obtained in this cohort with those of previous population surveys. METHODS: Using a microarray technique (ABCR400 gene chip), we screened all previously reported ABCA4 gene mutations in the genomic DNA of 27 patients from 21 unrelated Stargardt families whose phenotypes had been clinically evaluated using psychophysics and electrophysiological measurements. Furthermore, we performed denaturing high performance liquid chromatography whenever one or both mutant alleles failed to be detected using the ABCR gene chip. RESULTS: A total of 36 mutant alleles (out of the 54 tested) were identified in STGD patients, resulting in a detection rate of 67%. Two mutant alleles were present in 12 out of 21 STGD families (57%), whereas in four out of 21 (19%) of the families, only one mutant allele was found. We report the presence of 22 putative pathogenic alterations, including two sequence changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease-associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X). The great majority of the mutations were missense (72.7%). Seven frameshift variants (19.4%), three nonsense mutations (8.3%), and one splicing sequence change (2.7%) were also found in STGD chromosomes. The most prevalent pathologic variant was the missense mutation p.Leu11Pro. Present in 19% of the families, this mutation represents a quite high prevalence in comparison to other European populations. In addition, 23 polymorphisms were also identified, including four novel intronic sequence variants. CONCLUSIONS: To our knowledge, this study represents the first report of ABCA4 mutations in Portuguese STGD patients and provides further evidence of different mutation frequency across populations. Phenotypic characterization of novel putative mutations was addressed.

Retinal function in best macular dystrophy: relationship between electrophysiological, psychophysical, and structural measures of damage.

PURPOSE: To establish structure-function correlations across the visual field, to investigate disease progression in Best macular dystrophy (BMD), by correlating structural damage with retinal function as assessed by the combination of psychophysics and multifocal electrophysiology. METHODS: Spatial achromatic and chromatic contrast sensitivities (probing red-green and blue-yellow pathways) were assessed using custom-made psychophysical software to evaluate retinal damage in BMD and age-matched control eyes (n = 19 and n = 22, respectively). Neurosensory retinal dysfunction was also evaluated by means of multifocal electroretinography (mfERG). Correlation analysis was performed between functional parameters in BMD, clinical measures, and morphologic data obtained by optical coherence tomography (OCT). RESULTS: Significant peripheral impairment of retinal function, as measured by mfERG and spatial achromatic contrast sensitivity (CS) methods, was found in BMD. Furthermore, changes in thickness of the neurosensory retina, as measured by OCT, and reduced mfERG responses were also indicators of early loss in BMD and often occurred even with preserved visual acuity. Disease duration was significantly correlated with psychophysical deterioration in chromatic and achromatic tasks but not with mfERG measures. Interestingly, partial correlation analysis revealed a significant independent correlation with our CS measures. CONCLUSIONS: Novel topographic achromatic and chromatic CS methods can detect and quantify functional impairment in early stages of BMD, including the involvement of the peripheral retina and the central chromatic pathway, and can provide new pathophysiological information with added value in relation to electrophysiological and structural measures of damage.