Modulation of long-range neural synchrony reflects temporal limitations of visual attention in humans

Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little is known about how these areas interact to form a dynamic attentional network. We hypothesized that the network communicates by means of neural phase synchronization, and we used magnetoencephalography to study transient long-range interarea phase coupling in a well studied attentionally taxing dual-target task (attentional blink). Our results reveal that communication within the fronto-parieto-temporal attentional network proceeds via transient long-range phase synchronization in the beta band. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioral performance. Thus, we show how attentional limitations arise from the way in which the subsystems of the attentional network interact. The human brain faces an inestimable task of reducing a potentially overloading amount of input into a manageable flow of information that reflects both the current needs of the organism and the external demands placed on it. This task is accomplished via a ubiquitous construct known as “attention,” whose mechanism, although well characterized behaviorally, is far from understood at the neurophysiological level. Whereas attempts to identify particular neural structures involved in the operation of attention have met with considerable success (1-5) and have resulted in the identification of frontal, parietal, and temporal regions, far less is known about the interaction among these structures in a way that can account for the task-dependent successes and failures of attention. The goal of the present research was, thus, to unravel the means by which the subsystems making up the human attentional network communicate and to relate the temporal dynamics of their communication to observed attentional limitations in humans. A prime candidate for communication among distributed systems in the human brain is neural synchronization (for review, see ref. 6). Indeed, a number of studies provide converging evidence that long-range interarea communication is related to synchronized oscillatory activity (refs. 7-14; for review, see ref. 15). To determine whether neural synchronization plays a role in attentional control, we placed humans in an attentionally demanding task and used magnetoencephalography (MEG) to track interarea communication by means of neural synchronization. In particular, we presented 10 healthy subjects with two visual target letters embedded in streams of 13 distractor letters, appearing at a rate of seven per second. The targets were separated in time by a single distractor. This condition leads to the “attentional blink” (AB), a well studied dual-task phenomenon showing the reduced ability to report the second of two targets when an interval <500 ms separates them (16-18). Importantly, the AB does not prevent perceptual processing of missed target stimuli but only their conscious report (19), demonstrating the attentional nature of this effect and making it a good candidate for the purpose of our investigation. Although numerous studies have investigated factors, e.g., stimulus and timing parameters, that manipulate the magnitude of a particular AB outcome, few have sought to characterize the neural state under which “standard” AB parameters produce an inability to report the second target on some trials but not others. We hypothesized that the different attentional states leading to different behavioral outcomes (second target reported correctly or not) are characterized by specific patterns of transient long-range synchronization between brain areas involved in target processing. Showing the hypothesized correspondence between states of neural synchronization and human behavior in an attentional task entails two demonstrations. First, it needs to be demonstrated that cortical areas that are suspected to be involved in visual-attention tasks, and the AB in particular, interact by means of neural synchronization. This demonstration is particularly important because previous brain-imaging studies (e.g., ref. 5) only showed that the respective areas are active within a rather large time window in the same task and not that they are concurrently active and actually create an interactive network. Second, it needs to be demonstrated that the pattern of neural synchronization is sensitive to the behavioral outcome; specifically, the ability to correctly identify the second of two rapidly succeeding visual targets

To which extent can attention and/or modulation explains deficits in dyslexia?

This thesis investigates the visual deficits associated with developmental dyslexia, particularly that of visual attention. Visual attention has previously been investigated in a wide array of behavioural and psychophysical (amongst others) studies but not many have produced consistent findings. Attention processes are believed to play an integral part in depicting the overall "extent" of reading deficits in dyslexia, so it was of paramount importance to aim at such attention mechanisms in this research. The experiments in this thesis focused on signal enhancement and noise (distractor) exclusion. Given the flexibility of the visual search paradigms employed in this research, factors such as visual crowding and attention distribution was also investigated. The experiments systematically manipulated noise (by increasing distractor count, i.e. set-size), crowding (varying the spacing between distractors), attention allocation (use of peripheral cues to direct attention), and attention distribution (influence of one visual field over the other), all of which were tied to a critical factor, the "location/spatial/decisional uncertainty". Adults with dyslexia were: (i) able to modulate attention appropriately using peripheral pre-cues, (ii) severely affected by crowding, and (iii) unable to counteract increased set-sizes when post or un-cued, the latter signifying poor distractor (noise) suppression. By controlling for location uncertainty, the findings confirmed that adults with dyslexia were yet again affected by crowding and set-size, in addition to an asymmetric attention distribution. Confounding effects of ADHD symptoms did not explain a significant independent variance in performance, suggesting that the difficulty shown by adult dyslexics were not accounted for by co-morbid ADHD. Furthermore, the effects of crowding, set-size and asymmetric attention correlated significantly with literacy, but not ADHD measures. It is believed that a more diffuse and an asymmetric attention system (in dyslexia) to be the limiting factor concerning noise exclusion and attention distribution. The findings from this thesis add to the current understanding of the potential role of deficits in visual attention in dyslexia and in the literacy difficulties experienced by this population.

Exploring civil servant resistance to M-government:a story of transition and opportunities in Turkey

The concept of mobility, related to technology in particular, has evolved dramatically over the last two decades including: (i) hardware ranging from walkmans to Ipods, laptops to netbooks, PDAs to 3G mobile phone; (ii) software supporting multiple audio and video formats driven by ubiquitous mobile wireless access, WiMax, automations such as radio frequency ID tracking and location aware services. Against the background of increasing budget deficit, along with the imperative for efficiency gains, leveraging ICT and mobility promises for work related tasks, in a public administration context, in emerging markets, point to multiple possible paths. M-government transition involve both technological changes and adoption to deliver government services differently (e.g. 24/7, error free, anywhere to the same standards) but also the design of digital strategies including possibly competing m-government models, the re-shaping of cultural practices, the creation of m-policies and legislations, the structuring of m-services architecture, and progress regarding m-governance. While many emerging countries are already offering e-government services and are gearing-up for further m-government activities, little is actually known about the resistance that is encountered, as a reflection of civil servants' current standing, before any further macro-strategies are deployed. Drawing on the resistance and mobility literature, this chapter investigates how civil servants' behaviors, in an emerging country technological environment, through their everyday practice, react and resist the influence of m-government transition. The findings points to four main type of resistance namely: i) functional resistance; ii) ideological resistance; iii) market driven resistance and iv) geographical resistance. Policy implication are discussed in the specific context of emerging markets. © 2011, IGI Global.

Treating type 2 diabetes through insulin resistance

Type 2 diabetes is an insidious disorder, with micro and/or macrovascular and nervous damage occurring in many patients before diagnosis. This damage is caused by hyperglycaemia and the diverse effects of insulin resistance. Obesity, in particular central obesity, is a strong pre-disposing factor for type 2 diabetes. Skeletal muscle is the main site of insulin-stimulated glucose disposal and appears to be the first organ that becomes insulin resistant in the diabetic state, with later involvement of adipose tissue and the liver. This study has investigated the use of novel agents to ameliorate insulin-resistance in skeletal muscle as a means of identifying intervention sites against insulin resistance and of improving glucose uptake and metabolism by skeletal muscle. Glucose uptake was measured in vitro by cultured L6 myocytes and isolated muscles from normal and obese diabetic ob/ob mice, using either the tritiated non-metabolised glucose analogue 2-deoxy-D-glucose or by glucose disposal. Agents studied included lipoic acid, isoferulic acid, bradykinin, lipid mobilising factor (provisionally synonymous with Zinca2 glycoprotein) and the trace elements lithium, selenium and chromium. The putative role of TNFa in insulin resistance was also investigated. Lipoic acid improved insulin-stimulated glucose uptake in normal and insulin resistance murine muscles, as well as cultured myocytes. Isoferulic acid, bradykinin and LMF also produced a transient increase in glucose uptake in cultured myocytes. Physiological concentrations of TNFa were found to cause insulin resistance in cultured, but no in excised murine muscles. The effect of the M2 metabolite of the satiety-inducing agent sibutramine on lipolysis in excised murine and human adipocytes was also investigated. M2 increased lipolysis from normal lean and obese ob/ob mouse adipocytes. Arguably the most important observation was that M2 also increased the lipolytic rate in adipocytes from catecholamine resistant obese subjects. The studies reported in this thesis indicate that a diversity of agents can improve glucose uptake and ameliorate insulin resistance. It is likely that these agents are acting via different pathways. This thesis has also shown that M2 can induce lipolysis in both rodent and human adipocytes. M2 hence has potential to directly reduce adiposity, in addition to well documented effects via the central nervous system.

The Gilles de la Tourette Syndrome-Quality of Life Scale for children and adolescents (C&A-GTS-QOL):development and validation of the Italian version

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a chronic childhood-onset neuropsychiatric disorder with a significant impact on patients' health-related quality of life (HR-QOL). Cavanna et al. (Neurology 2008; 71: 1410-1416) developed and validated the first disease-specific HR-QOL assessment tool for adults with GTS (Gilles de la Tourette Syndrome-Quality of Life Scale, GTS-QOL). This paper presents the translation, adaptation and validation of the GTS-QOL for young Italian patients with GTS. METHODS: A three-stage process involving 75 patients with GTS recruited through three Departments of Child and Adolescent Neuropsychiatry in Italy led to the development of a 27-item instrument (Gilles de la Tourette Syndrome-Quality of Life Scale in children and adolescents, C&A-GTS-QOL) for the assessment of HR-QOL through a clinician-rated interview for 6-12 year-olds and a self-report questionnaire for 13-18 year-olds. RESULTS: The C&A-GTS-QOL demonstrated satisfactory scaling assumptions and acceptability. Internal consistency reliability was high (Cronbach's alpha > 0.7) and validity was supported by interscale correlations (range 0.4-0.7), principal-component factor analysis and correlations with other rating scales and clinical variables. CONCLUSIONS: The present version of the C&A-GTS-QOL is the first disease-specific HR-QOL tool for Italian young patients with GTS, satisfying criteria for acceptability, reliability and validity. © 2013 - IOS Press and the authors. All rights reserved.

Cerebellar morphology in developmental dyslexia

Recent evidence has suggested cerebellar anomalies in developmental dyslexia. Therefore, we investigated cerebellar morphology in subjects with documented reading disabilities. We obtained T1-weighted magnetic resonance images in the coronal and sagittal planes from 11 males with prior histories of developmental dyslexia, and nine similarly-aged male controls. Proton magnetic resonance spectra (TE=136 ms, TR=2.4 s) were obtained bilaterally in the cerebellum. Phonological decoding skill was measured using non-word reading. Handedness was assessed using both the Annett questionnaire of hand preference and Annett’s peg moving task. Cerebellar symmetry was observed in the dyslexics but there was significant asymmetry (right grey matter>left grey matter) in controls. The interpretation of these results depended whether a motor- or questionnaire-based method was used to determine handedness. The degree of cerebellar symmetry was correlated with the severity of dyslexics’ phonological decoding deficit. Those with more symmetric cerebella made more errors on a nonsense word reading measure of phonological decoding ability. Left cerebellar metabolite ratios were shown to correlate significantly with the degree of cerebellar asymmetry (P<0.05) in controls. This relationship was absent in developmental dyslexics. Cerebellar morphology reflects the higher degree of symmetry found previously in the temporal and parietal cortex of dyslexics. The relationship of cerebellar asymmetry to phonological decoding ability and handedness, together with our previous finding of altered metabolite ratios in the cerebellum of dyslexics, lead us to suggest that there are alterations in the neurological organisation of the cerebellum which relate to phonological decoding skills, in addition to motor skills and handedness.

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease.

Attention deficits in dyslexia:Evidence for an automatisation deficit?

Both attentional difficulties and rapid processing deficits have recently been linked with dyslexia. We report two studies comparing the performance of dyslexic and control teenagers on attentional tasks. The two studies were based on two different conceptions of attention. Study 1 employed a design that allowed three key components of attention - focusing, switching, and sustaining - to be investigated separately. One hypothesis under investigation was that rapid processing problems - in particular impaired ability to switch attention rapidly - might be associated with dyslexia. However, although dyslexic participants were significantly less accurate than their controls in a condition where they had to switch attention between two target types, the nature of the deficit suggested that the problem was not in switching attention per se. Thus, in Study 2, we explored an alternative interpretation of the Study 1 results in terms of the classic capacity-limited models of "central" attention. We contrasted two hypotheses: (1) that dyslexic teenagers have reduced cognitive resources versus (2) that they suffer from a general impairment in the ability to automatise basic skills. To investigate the automaticity of the shape recognition component of the task a similar attention paradigm to that used in Study 1 was employed, but using degraded, as well as intact, stimuli. It was found that stimulus degradation led to relatively less impairment for dyslexic than for matched control groups. The results support the hypothesis that dyslexic people suffer from a general impairment in the ability to automatise skills - in this case the skill of automatic shape recognition.

Impaired sustained attention and executive dysfunction:bipolar disorder versus depression-specific markers of affective disorders

Objective - To identify neurocognitive measures that could be used as objective markers of bipolar disorder. Methods - We examined executive function, sustained attention and short-term memory as neurocognitive domains in 18 participants with bipolar disorder in euthymic state (Beuth), 14 in depressed state (Bdep), 20 with unipolar depression (Udep) and 28 healthy control participants (HC). We conducted four-group comparisons followed by relevant post hoc analyses. Results - Udep and Bdep, but not Beuth showed impaired executive function (p = 0.045 and p = 0.046, respectively). Both Bdep and Beuth, but not Udep, showed impaired sustained attention (p = 0.001 and p = 0.045, respectively). The four groups did not differ significantly on short-term memory. Impaired sustained attention and executive dysfunction were not associated with depression severity, duration of illness and age of illness onset. Only a small number of abnormal neurocognitive measures were associated with medication in Bdep and Beuth. Conclusion - Impaired sustained attention appears specific to bipolar disorder and present in both Beuth and Bdep; it may represent an objective marker of bipolar disorder. Executive dysfunction by contrast, appears to be present in Udep and Bdep and likely represents a marker of depression.

The impact of general intellectual ability and white matter volume on the functional outcome of patients with bipolar disorder and their relatives

Background: There is substantial evidence that cognitive deficits and brain structural abnormalities are present in patients with Bipolar Disorder (BD) and in their first-degree relatives. Previous studies have demonstrated associations between cognition and functional outcome in BD patients but have not examined the role of brain morphological changes. Similarly, the functional impact of either cognition or brain morphology in relatives remains unknown. Therefore we focused on delineating the relationship between psychosocial functioning, cognition and brain structure, in relation to disease expression and genetic risk for BD. Methods: Clinical, cognitive and brain structural measures were obtained from 41 euthymic BD patients and 50 of their unaffected first-degree relatives. Psychosocial function was evaluated using the General Assessment of Functioning (GAF) scale. We examined the relationship between level of functioning and general intellectual ability (IQ), memory, attention, executive functioning, symptomatology, illness course and total gray matter, white matter and cerebrospinal fluid volumes. Limitations: Cross-sectional design. Results: Multiple regression analyses revealed that IQ, total white matter volume and a predominantly depressive illness course were independently associated with functional outcome in BD patients, but not in their relatives, and accounted for a substantial proportion (53%) of the variance in patients' GAF scores. There were no significant domain-specific associations between cognition and outcome after consideration of IQ. Conclusions: Our results emphasise the role of IQ and white matter integrity in relation to outcome in BD and carry significant implications for treatment interventions. © 2010 Elsevier B.V.