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Background Transcranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound. Objectives We aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds. Methods We used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT+ stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials. Results Compared with sham and control site stimulation, TUS to hMT+ improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation. Conclusions The results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.

AIM: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC). METHOD: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2. RESULTS: Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence. INTERPRETATION: Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy. WHAT THIS PAPER ADDS: Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC.

Background and Purpose—Lesion expansion in the week after acute stroke involves both infarct growth (IG) and anatomic distortion (AD) because of edema and hemorrhage. Enabling separate quantification would allow clinical trials targeting these distinct pathological processes. We developed an objective and automated approach to quantify these processes at 24 hours and 1 week. Methods—Patients with acute ischemic stroke were scanned at presentation, 24 hours, and 1 week in a magnetic resonance imaging (MRI) cohort study. IG and AD were calculated from follow-up lesion masks after linear and nonlinear registration to a presenting MRI scan. Performance of IG and AD was compared with edema quantified using cerebrospinal fluid displacement. The use of alternative reference images to define AD, including template MRI, mirrored MRI, and presenting computed tomographic scan, was explored. Results—Thirty-seven patients with nonlacunar stroke were included. AD was responsible for 20% and 36% of lesion expansion at 24 hours (n=30) and 1 week (n=28). Registration-defined IG and AD compared favorably with edema quantified using cerebrospinal fluid displacement, particularly at smaller infarct volumes. Presenting computed tomographic imaging was the preferred alternative reference image to presenting MRI for measuring AD. Conclusions—The contributions of IG and AD to lesion expansion can be measured separately over time through the use of image registration. This approach can be used to combine imaging outcome data from computed tomography and MRI.

Objective: Accurate representation of final infarct volume is essential for assessing the efficacy of stroke interventions in imaging-based studies. This study defines the impact of image registration methods used at different timepoints following stroke, and the implications for infarct definition in stroke research. Methods: Patients presenting with acute ischemic stroke were imaged serially using magnetic resonance imaging. Infarct volume was defined manually using four metrics: 24-h b1000 imaging; 1-week and 1-month T2-weighted FLAIR; and automatically using predefined thresholds of ADC at 24 h. Infarct overlap statistics and volumes were compared across timepoints following both rigid body and nonlinear image registration to the presenting MRI. The effect of nonlinear registration on a hypothetical trial sample size was calculated. Results: Thirty-seven patients were included. Nonlinear registration improved infarct overlap statistics and consistency of total infarct volumes across timepoints, and reduced infarct volumes by 4.0 mL (13.1%) and 7.1 mL (18.2%) at 24 h and 1 week, respectively, compared to rigid body registration. Infarct volume at 24 h, defined using a predetermined ADC threshold, was less sensitive to infarction than b1000 imaging. 1-week T2-weighted FLAIR imaging was the most accurate representation of final infarct volume. Nonlinear registration reduced hypothetical trial sample size, independent of infarct volume, by an average of 13%. Interpretation: Nonlinear image registration may offer the opportunity of improving the accuracy of infarct definition in serial imaging studies compared to rigid body registration, helping to overcome the challenges of anatomical distortions at subacute timepoints, and reducing sample size for imaging-based clinical trials.

Background and Purpose—Perfusion-weighted imaging is used to select patients with acute ischemic stroke for intervention, but knowledge of cerebral perfusion can also inform the understanding of ischemic injury. Arterial spin labeling allows repeated measurement of absolute cerebral blood flow (CBF) without the need for exogenous contrast. The aim of this study was to explore the relationship between dynamic CBF and tissue outcome in the month after stroke onset. Methods—Patients with nonlacunar ischemic stroke underwent ≤5 repeated magnetic resonance imaging scans at presentation, 2 hours, 1 day, 1 week, and 1 month. Imaging included vessel-encoded pseudocontinuous arterial spin labeling using multiple postlabeling delays to quantify CBF in gray matter regions of interest. Receiver–operator characteristic curves were used to predict tissue outcome using CBF. Repeatability was assessed in 6 healthy volunteers and compared with contralateral regions of patients. Diffusion-weighted and T2-weighted fluid attenuated inversion recovery imaging were used to define tissue outcome. Results—Forty patients were included. In contralateral regions of patients, there was significant variation of CBF between individuals, but not between scan times (mean±SD: 53±42 mL/100 g/min). Within ischemic regions, mean CBF was lowest in ischemic core (17±23 mL/100 g/min), followed by regions of early (21±26 mL/100 g/min) and late infarct growth (25±35 mL/100 g/min; ANOVA P Conclusions—Knowledge of perfusion dynamics partially explained tissue fate. Factors such as metabolism and tissue susceptibility are also likely to influence tissue outcome.

Amide proton transfer (APT) imaging is a pH mapping method based on the chemical exchange saturation transfer phenomenon that has potential for penumbra identification following stroke. The majority of the literature thus far has focused on generating pH‐weighted contrast using magnetization transfer ratio asymmetry analysis instead of quantitative pH mapping. In this study, the widely used asymmetry analysis and a model‐based analysis were both assessed on APT data collected from healthy subjects (n = 2) and hyperacute stroke patients (n = 6, median imaging time after onset = 2 hours 59 minutes). It was found that the model‐based approach was able to quantify the APT effect with the lowest variation in grey and white matter (≤ 13.8 %) and the smallest average contrast between these two tissue types (3.48 %) in the healthy volunteers. The model‐based approach also performed quantitatively better than the other measures in the hyperacute stroke patient APT data, where the quantified APT effect in the infarct core was consistently lower than in the contralateral normal appearing tissue for all the patients recruited, with the group average of the quantified APT effect being 1.5 ± 0.3 % (infarct core) and 1.9 ± 0.4 % (contralateral). Based on the fitted parameters from the model‐based analysis and a previously published pH and amide proton exchange rate relationship, quantitative pH maps for hyperacute stroke patients were generated, for the first time, using APT imaging. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Huge progress has been made in recognising and supporting lesbian, gay, bisexual and transgender (LGBT) people in Ireland. In the space of twenty years we have seen the decriminalisation of homosexuality and the introduction of a sophisticated equality infrastructure, with the Employment Equality Act 1998 and the Equal Status Act 2000 having been at the forefront internationally in naming sexual orientation as a specific equality ground and in extending its scope outside the field of employment. More recently, in 2010 comprehensive Civil Partnership legislation was introduced and the Government is determined to bring forward legislation later this year to provide for the recognition of the acquired gender of transgender people, on the basis of the recommendations of the Gender Recognition Advisory Group published in June. This report is the first comprehensive study of the lives of older LGBT people in Ireland. It offers unique insights into the lives of those people who have lived through and been most personally affected by these changes in Irish society. It shows the negative consequences for LGBT people of living through a period where a fundamental aspect of their identity - to be themselves and to live openly and securely with the person they love - was stigmatised, criminalised or even viewed as an illness.