The Effects of Aging on Orientation Discrimination

Visual perception relies on low-level encoding of local orientation. Recent studies show an age-dependent impairment in orientation discrimination of stimuli embedded in external noise, suggesting that encoding of orientation is inefficient in older adults. In the present study we ask whether aging also reduces decoding, i.e., selecting the neural representations of target orientation while discarding those conflicting with it. We compared younger and older participants capability (mean age 24 and 68 years respectively) in discriminating whether the orientation of a Gabor target was left or right from the vertical. We measured (d0), an index of discrimination sensitivity, for orientation offset ranging from 1 to 12. In the isolated target condition, d0 was reduced by aging and, in the older group, did not increase with orientation offset, thus resulting in a larger group difference at large than small orientation offsets from the vertical. Moreover, oriented elements in the background impaired more discrimination in the older group. However, distractors reduced more d0 when target-background orientation offset was large than when target and flanker had similar orientation, indicating that the effect of the background was not local, i.e., due to target inhibition by similarly oriented flankers. Altogether, these results indicate that aging reduces the efficiency in discarding the response to orientations differing from the target. Our results suggest that neural decision-making mechanisms, involving not only signal enhancement but also non-signal inhibition, become inefficient with age. This suggestion is consistent with the neurophysiological evidence of inefficient visual cortical inhibition in aging

EEG-based investigation of cortical activity during Postural Control

The postural control system regulates the ability to maintain a stable upright stance and to react to changes in the external environment. Although once believed to be dominated by low-level reflexive mechanisms, mounting evidence has highlighted a prominent role of the cortex in this process. Nevertheless, the high-level cortical mechanisms involved in postural control are still largely unexplored. The aim of this thesis is to use electroencephalography, a widely used and non-invasive neuroimaging tool, to shed light on the cortical mechanisms which regulate postural control and allow balance to be preserved in the wake of external disruptions to one’s quiet stance. EEG activity has been initially analysed during a well-established postural task - a sequence of proprioceptive stimulations applied to the calf muscles to induce postural instability – traditionally used to examine the posturographic response. Preliminary results, obtained through a spectral power analysis of the data, highlighted an increased activation in several cortical areas, as well as different activation patterns in the two tested experimental conditions: open and closed eyes. An improved experimental protocol has then been developed, allowing a more advanced data analysis based on source reconstruction and brain network analysis techniques. Using this new approach, it was possible to characterise with greater detail the topological structure of cortical functional connections during the postural task, as well as to draw a connection between quantitative network metrics and measures of postural performance. Finally, with the integration of electromyography in the experimental protocol, we were able to gain new insights into the cortico-muscular interactions which direct the muscular response to a postural challenge. Overall, the findings presented in this thesis provide further evidence of the prominent role played by the cortex in postural control. They also prove how novel EEG-based brain network analysis techniques can be a valid tool in postural research and offer promising perspectives for the integration of quantitative cortical network metrics into clinical evaluation of postural impairment.Kerfi stöðustjórnunar er afturvirkt stýrikerfi sem vinnur stöðugt að því að viðhalda uppréttri stöðu líkamans og bregðast við ójafnvægi. Vaxandi þekking á undanförnum árum hefur lýst því að úrvinnsla þessara upplýsinga á sér stað á öllum stigum miðtaugakerfisins, þá sérstaklega barkarsvæði heilahvela. Engu að síður, er nákvæmu hlutverk heilabarkar við stöðustjórnun enn óljóst að mörgu leyti. Tilgangur þessa verkefnis var að rannsaka nánar hlutverk heilabarkar við truflun og áreiti á kerfi stöðustjórnarinnar, með notkun hágæða heilarafrits (EEG). Við byrjuðum á því að mæla heilarit einstaklinga meðan á þekktri líkamsstöðu-æfingu stóð, til þess að skoða svörun líkamans við röð titringsáreita sem beitt var á kálfavöðvana til að framkalla óstöðugleika. Bráðabirgðaniðurstöður fengnar með PSD-aðferð (power spectral analysis) leiddu í ljós aukna virkni á ákveðnum svæðum í heilaberki og sérstakt viðbragðsmynstur við að framkvæma æfinguna, annars vegar með lokuð augu og hins vegar opin augu. Rannsókn okkar hélt áfram með nýrri og þróaðari tækni sem gerði okkur kleift að framkvæma fullkomnari greiningaraðferðir til að túlka, greina og skilja merki frá heilaritnu. Með fullkomnari greiningaraðferðum var hægt að lýsa með nákvæmari hætti staðfræðilega uppbyggingu starfrænna tenginga í heilaberki meðan á líkamsstöðu æfingunni stóð, sem og að draga tengsl á milli megindlegra netmælinga og mælinga á líkamsstöðu. Að lokum bætist við vöðvarafritsmæling við aðferðafræðina, sem gaf okkur innsýn inn í samskipti heilabarka og vöðvana sem stýra vöðvaviðbrögðum og viðhalda líkamsstöðu við utanaðkomandi áreiti. Á heildina litið gefa niðurstöðurnar sem settar eru fram í þessari ritgerð enn sterkari vísbendingar um það áberandi hlutverk sem heilabörkurinn gegnir við stjórnun líkamsstöðu. Niðurstöðurnar sanna einnig hvernig ný aðferð á greiningu á tengslaneti heilans sem byggir á heilariti getur verið gilt tæki í líkamsstöðu rannsóknum og er nytsamlegt tól fyrir mælingar á heilakerfisneti í klínískt mat á skerðingu líkamsstöðu

Effects of Aging on Visual Contour Integration and Segmentation

PURPOSE. Perception of circular disconnected contours requires the integration of relevant local orientation information across space and the suppression of irrelevant orientations. Using a detection of deviation from circularity (DFC) task, the present study examined whether the efficiency of either integrative or suppressive visual mechanisms, or both, declines with age. METHODS. Younger and older observers' sensitivities in detecting the DFC of a contour formed by Gabors were compared in three conditions: when all elements were oriented tangentially to the contour, with and without the presence of randomly oriented background noise; and when they had alternated tangential and orthogonal orientations, without background noise. RESULTS. In agreement with previous studies, the authors found that younger observers were not impaired in the mixed condition with respect to the tangential condition, suggesting the involvement of a high-level mechanism responding to the global closure information provided by tangential local orientations, even if they are interspersed with orthogonal ones. Instead, older observers were specifically impaired in the mixed condition, suggesting a reduced capability of suppressing nontangential information along the contour, and were also less efficient in suppressing irrelevant orientations in the background. CONCLUSIONS. These results support the suggestion that, whereas integrative mechanisms are not affected by age, suppressive mechanisms are. (Invest Ophthalmol Vis Sci. 2011;52: 3955‐3961) DOI:10.1167/iovs.10-543

Perceptual learning improves contrast sensitivity, visual acuity, and foveal crowding in amblyopia

BACKGROUND: Amblyopic observers present abnormal spatial interactions between a low-contrast sinusoidal target and high-contrast collinear flankers. It has been demonstrated that perceptual learning (PL) can modulate these low-level lateral interactions, resulting in improved visual acuity and contrast sensitivity. OBJECTIVE: We measured the extent and duration of generalization effects to various spatial tasks (i.e., visual acuity, Vernier acuity, and foveal crowding) through PL on the target's contrast detection. METHODS: Amblyopic observers were trained on a contrast-detection task for a central target (i.e., a Gabor patch) flanked above and below by two high-contrast Gabor patches. The pre- and post-learning tasks included lateral interactions at different target-to-flankers separations (i.e., 2, 3, 4, 8λ) and included a range of spatial frequencies and stimulus durations as well as visual acuity, Vernier acuity, contrast-sensitivity function, and foveal crowding. RESULTS: The results showed that perceptual training reduced the target's contrast-detection thresholds more for the longest target-to-flanker separation (i.e., 8λ). We also found generalization of PL to different stimuli and tasks: contrast sensitivity for both trained and untrained spatial frequencies, visual acuity for Sloan letters, and foveal crowding, and partially for Vernier acuity. Follow-ups after 5-7 months showed not only complete maintenance of PL effects on visual acuity and contrast sensitivity function but also further improvement in these tasks. CONCLUSION: These results suggest that PL improves facilitatory lateral interactions in amblyopic observers, which usually extend over larger separations than in typical foveal vision. The improvement in these basic visual spatial operations leads to a more efficient capability of performing spatial tasks involving high levels of visual processing, possibly due to the refinement of bottom-up and top-down networks of visual areas

EEG-based investigation of cortical activity during Postural Control

The postural control system regulates the ability to maintain a stable upright stance and to react to changes in the external environment. Although once believed to be dominated by low-level reflexive mechanisms, mounting evidence has highlighted a prominent role of the cortex in this process. Nevertheless, the high-level cortical mechanisms involved in postural control are still largely unexplored. The aim of this thesis is to use electroencephalography, a widely used and non-invasive neuroimaging tool, to shed light on the cortical mechanisms which regulate postural control and allow balance to be preserved in the wake of external disruptions to one’s quiet stance. EEG activity has been initially analysed during a well-established postural task - a sequence of proprioceptive stimulations applied to the calf muscles to induce postural instability – traditionally used to examine the posturographic response. Preliminary results, obtained through a spectral power analysis of the data, highlighted an increased activation in several cortical areas, as well as different activation patterns in the two tested experimental conditions: open and closed eyes. An improved experimental protocol has then been developed, allowing a more advanced data analysis based on source reconstruction and brain network analysis techniques. Using this new approach, it was possible to characterise with greater detail the topological structure of cortical functional connections during the postural task, as well as to draw a connection between quantitative network metrics and measures of postural performance. Finally, with the integration of electromyography in the experimental protocol, we were able to gain new insights into the cortico-muscular interactions which direct the muscular response to a postural challenge. Overall, the findings presented in this thesis provide further evidence of the prominent role played by the cortex in postural control. They also prove how novel EEG-based brain network analysis techniques can be a valid tool in postural research and offer promising perspectives for the integration of quantitative cortical network metrics into clinical evaluation of postural impairment

RET codon 609 mutations: a contribution for better clinical managing

Medullary thyroid carcinoma currently accounts for 5–8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC

Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p=0.03, r=−0.3); advanced stage (p=0.001); persistent disease (p=0.001); progressive disease (p=0.002); and disease-related death (p=0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p=0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p=0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

CTLA-4 and PD-1 ligand gene expression in epithelial thyroid cancers

The dysregulation of PD-1 ligands (PD-L1 and PD-L2) and CTLA-4 ligands (CD80 and CD86) represents a tumor strategy to escape the immune surveillance. Here, the expression of PD-L1, PD-L2, CD80 and CD86 was evaluated at mRNA level in 94 patients affected by papillary thyroid carcinoma (PTC) and 11 patients affected by anaplastic thyroid carcinoma (ATC). Variations in the mRNAs in PTC patients were then correlated with clinicopathological features. The expression of all genes was deregulated in PTC and ATC tissues compared to normal tissues. In particular, the down-regulation of CD80 was observed in above all ATC. In addition, the increased expression of CD80 associated to longer disease-free survival in PTC. Higher expression of PD-L1 associated with the classical histological variant and with the presence of BRAFV600E mutation in PTC. The increased PD-L2 expression correlated with BRAFV600E mutation and lymph node metastasis, while its lower expression correlated with the follicular PTC variant. The latter was also associated with the CD80 down-regulation, which was also related to the absence of lymph node metastasis. In conclusion, we documented the overall dysregulation of PD-1 and CTLA-4 ligands in PTC and ATC tissues and a possible prognostic value for CD80 gene expression in PTC