Search results
Found 8303 matches for
Accelerating Heritability, Genetic Correlation, and Genome-Wide Association Imaging Genetic Analyses in Complex Pedigrees.
National and international biobanking efforts led to the collection of large and inclusive imaging genetics datasets that enable examination of the contribution of genetic and environmental factors to human brains in illness and health. High-resolution neuroimaging (~104-6 voxels) and genetic (106-8 single nucleotide polymorphic [SNP] variants) data are available in statistically powerful (N = 103-5) epidemiological and disorder-focused samples. Performing imaging genetics analyses at full resolution afforded in these datasets is a formidable computational task even under the assumption of unrelatedness among the subjects. The computational complexity rises as ~N2-3 (where N is the sample size), when accounting for relatedness among subjects. We describe fast, non-iterative simplifications to accelerate classical variance component (VC) methods including heritability, genetic correlation, and genome-wide association in dense and complex empirical pedigrees. These approaches linearize (from N2-3 to N~1) computational effort while maintaining fidelity (r ~ 0.95) with the VC results and take advantage of parallel computing provided by central and graphics processing units (CPU and GPU). We show that the new approaches lead to a 104- to 106-fold reduction in computational complexity-making voxel-wise heritability, genetic correlation, and genome-wide association studies (GWAS) analysis practical for large and complex samples such as those provided by the Amish and Human Connectome Projects (N = 406 and 1052 subjects, respectively) and UK Biobank (N = 31,681). These developments are shared in open-source, SOLAR-Eclipse software.
Pramipexole for the Treatment of Depression: Efficacy and Mechanisms.
Dopaminergic mechanisms are a plausible treatment target for patients with clinical depression but are relatively underexplored in conventional antidepressant medications. There is continuing interest in the potential antidepressant effects of the dopamine receptor agonist, pramipexole, with data from both case series and controlled trials indicating that this agent may produce benefit for patients with difficult-to-treat depression. Pramipexole's therapeutic utility in depression is likely to be expressed through alterations in reward mechanisms which are strongly influenced by dopamine pathways and are known to function abnormally in depressed patients. Our work in healthy participants using brain imaging in conjunction with computational modelling suggests that repeated pramipexole facilitates reward learning by inhibiting value decay. This mechanism needs to be confirmed in larger clinical trials in depressed patients. Such studies will also allow assessment of whether baseline performance in reward learning in depression predicts therapeutic response to pramipexole treatment.
The neural correlates of texture perception: A systematic review and activation likelihood estimation meta-analysis of functional magnetic resonance imaging studies.
INTRODUCTION: Humans use discriminative touch to perceive texture through dynamic interactions with surfaces, activating low-threshold mechanoreceptors in the skin. It was largely assumed that texture was processed in primary somatosensory regions in the brain; however, imaging studies indicate heterogeneous patterns of brain activity associated with texture processing. METHODS: To address this, we conducted a coordinate-based activation likelihood estimation meta-analysis of 13 functional magnetic resonance imaging studies (comprising 15 experiments contributing 228 participants and 275 foci) selected by a systematic review. RESULTS: Concordant activations for texture perception occurred in the left primary somatosensory and motor regions, with bilateral activations in the secondary somatosensory, posterior insula, and premotor and supplementary motor cortices. We also evaluated differences between studies that compared touch processing to non-haptic control (e.g., rest or visual control) or those that used haptic control (e.g., shape or orientation perception) to specifically investigate texture encoding. Studies employing a haptic control revealed concordance for texture processing only in the left secondary somatosensory cortex. Contrast analyses demonstrated greater concordance of activations in the left primary somatosensory regions and inferior parietal cortex for studies with a non-haptic control, compared to experiments accounting for other haptic aspects. CONCLUSION: These findings suggest that texture processing may recruit higher order integrative structures, and the secondary somatosensory cortex may play a key role in encoding textural properties. The present study provides unique insight into the neural correlates of texture-related processing by assessing the influence of non-textural haptic elements and identifies opportunities for a future research design to understand the neural processing of texture.
Head circumference and intelligence, schooling, employment, and income: a systematic review.
BACKGROUND: No consensus exists about the role of head circumference in identifying children at risk of suboptimal development. The objective of this study was to evaluate the association between head circumference and intelligence, schooling, employment, and income. The review 1) summarizes the overall evidence and 2) restricts the evidence to a subset of articles that met minimum quality criteria. METHODS: PubMed, Web of Science, PsycINFO, LILACS, CINAHL, WHO Institutional Repository for Information Sharing and UNICEF Innocenti were searched to identify published studies. Cohort, case-control or cross-sectional studies which evaluated the associations of interest in the general population, premature babies, babies with low birth weight or small for gestational age were included; head circumference must have been measured before the age of 20 years. Two reviewers independently performed study selection, data extraction and quality assessments. RESULTS: Of 2521 records identified, 115 were included and 21 met the minimum quality criteria. Ninety studies investigated if early measures of head circumference predict later outcomes and 25 studies measured head circumference and the outcome at the same timepoint; 78 studies adjusted the head circumference for age and sex. We identified large heterogeneity and inconsistency in the effect measures and data reported across studies. Despite the relatively large number of included articles, more than 80% presented serious limitations such as lack of adjustment for confounding and severe selection bias. Considering the subset of articles which met the minimum quality criteria, 12 of 16 articles showed positive association between head circumference and intelligence in the general population. However, in premature babies, 2 of 3 articles showed no clear effect. Head circumference was positively associated with academic performance in all investigated samples (5 of 5 articles). No article which evaluated educational attainment and employment met the minimum quality criteria, but the association between head circumference and these outcomes seems to be positive. CONCLUSIONS: Larger head circumferences are positively associated with higher levels of intelligence and academic performance in the general population, but there is evidence of non-linearity in those associations. Identifying a group of children in higher risk for worse outcomes by a simple and inexpensive tool could provide an opportunity to mitigate these negative effects. Further research is needed for a deeper understanding of the whole distribution of head circumference and its effect in premature babies. Authors should consider the non-linearity of the association in the data analysis. TRIAL REGISTRATION: Association between head circumference and intelligence, educational attainment, employment, and income: A systematic review, CRD42021289998 .
Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD.
There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.
Neurochemistry and functional connectivity in the brain of people with Charles Bonnet syndrome.
BACKGROUND: Charles Bonnet syndrome (CBS) is a condition in which people with vision loss experience complex visual hallucinations. These complex visual hallucinations may be caused by increased excitability in the visual cortex that are present in some people with vision loss but not others. OBJECTIVES: We aimed to evaluate the association between γ-aminobutyric acid (GABA) in the visual cortex and CBS. We also tested the relationship among visually evoked responses, functional connectivity, and CBS. DESIGN: This is a prospective, case-controlled, cross-sectional observational study. METHODS: We applied 3-Tesla magnetic resonance spectroscopy, as well as task-based and resting state (RS) connectivity functional magnetic resonance imaging in six participants with CBS and six controls without CBS. GABA+ was measured in the early visual cortex (EVC) and in the lateral occipital cortex (LOC). Participants also completed visual acuity and cognitive tests, and the North-East Visual Hallucinations Interview. RESULTS: The two groups were well-matched for age, gender, visual acuity and cognitive scores. There was no difference in GABA+ levels between groups in the visual cortex. Most participants showed the expected blood oxygenation level dependent (BOLD) activation to images of objects and the phase-scrambled control. Using a fixed effects analysis, we found that BOLD activation was greater in participants with CBS compared to controls. Analysis of RS connectivity with LOC and EVC showed little difference between groups. A fixed effects analysis showed a correlation between the extent of functional connectivity with LOC and hallucination strength. CONCLUSION: Overall, our results provide no strong evidence for an association between GABAergic inhibition in the visual cortex and CBS. We only found subtle differences in visual function and connectivity between groups. These findings suggest that the neurochemistry and visual connectivity for people with Charles Bonnet hallucinations are comparable to a sight loss population. Differences between groups may emerge when investigating subtle and transient changes that occur at the time of visual hallucinations.
Working memory as a representational template for reinforcement learning.
Working memory (WM) and reinforcement learning (RL) both influence decision-making, but how they interact to affect behaviour remains unclear. We assessed whether RL is influenced by the format of visual stimuli held in WM, either feature-based or unified, object-based representations. In a pre-registered paradigm, participants learned stimulus-action combinations that provided reward through 80% probabilistic feedback. In parallel, participants retained the RL stimulus in WM and were asked to recall this stimulus after each RL choice. Crucially, the format of representation probed in WM was manipulated, with blocks encouraging either separate features or bound objects to be remembered. Incentivising a feature-based WM representation facilitated feature-based learning, shown by an improved choice strategy. This reveals a role of WM in providing sustained internal representations that are harnessed by RL, providing a framework by which these two cognitive processes cooperate.
Impaired striatal glutathione-ascorbate metabolism induces transient dopamine increase and motor dysfunction.
Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington's disease (HD), hyperdopaminergia-probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)-is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione-ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance.
Rehabilitating homonymous visual field deficits: white matter markers of recovery-stage 1 registered report.
Damage to the primary visual cortex (V1) or its afferent white matter tracts results in loss of vision in the contralateral visual field that can present as homonymous visual field deficits. Recent evidence suggests that visual training in the blind field can partially reverse blindness at trained locations. However, the efficacy of visual training to improve vision is highly variable across subjects, and the reasons for this are poorly understood. It is likely that variance in residual functional or structural neural circuitry following the insult may underlie the variation among patients. Many patients with visual field deficits retain residual visual processing in their blind field, termed 'blindsight', despite a lack of awareness. Previous research indicates that an intact structural and functional connection between the dorsal lateral geniculate nucleus (dLGN) and the human extrastriate visual motion-processing area (hMT+) is necessary for blindsight to occur. We therefore predict that changes in this white matter pathway will underlie improvements in motion discrimination training. Twenty stroke survivors with unilateral, homonymous field defects from retro-geniculate brain lesions will complete 6 months of motion discrimination training at home. Visual training will involve performing two daily sessions of a motion discrimination task, at two non-overlapping locations in the blind field, at least 5 days per week. Motion discrimination and integration thresholds, Humphrey perimetry and structural and diffusion-weighted MRI will be collected pre- and post-training. Changes in fractional anisotropy will be analysed in two visual tracts: (i) between the ipsilesional dLGN and hMT+ and (ii) between the ipsilesional dLGN and V1. The (non-visual) tract between the ventral posterior lateral nucleus of the thalamus (VPL) and the primary somatosensory cortex (S1) will be analysed as a control. Tractographic changes will be compared to improvements in motion discrimination and Humphrey perimetry-derived metrics. We predict that (i) improved motion discrimination performance will be directly related to increased fractional anisotropy in the pathway between ipsilesional dLGN and hMT+ and (ii) improvements in Humphrey perimetry will be related to increased fractional anisotropy in the dLGN-V1 pathway. There should be no relationship between behavioural measures and changes in fractional anisotropy in the VPL-S1 pathway. This study has the potential to lead to greater understanding of the white matter microstructure of pathways underlying the behavioural outcomes resulting from visual training in retro-geniculate strokes. Understanding the neural mechanisms that underlie visual rehabilitation is fundamental to the development of more targeted and thus effective treatments for this underserved patient population.
Rehabilitating homonymous visual field deficits: white matter markers of recovery-stage 2 registered report.
Damage to the primary visual cortex or its afferent white matter tracts results in loss of vision in the contralateral visual field that can present as homonymous visual field deficits. Evidence suggests that visual training in the blind field can partially reverse blindness at trained locations. However, the efficacy of visual training is highly variable across participants, and the reasons for this are poorly understood. It is likely that variance in residual neural circuitry following the insult may underlie the variation among patients. Many stroke survivors with visual field deficits retain residual visual processing in their blind field despite a lack of awareness. Previous research indicates that intact structural and functional connections between the dorsal lateral geniculate nucleus and the human extrastriate visual motion-processing area hMT+ are necessary for blindsight to occur. We therefore hypothesized that changes in this white matter pathway may underlie improvements resulting from motion discrimination training. Eighteen stroke survivors with long-standing, unilateral, homonymous field defects from retro-geniculate brain lesions completed 6 months of visual training at home. This involved performing daily sessions of a motion discrimination task, at two non-overlapping locations in the blind field, at least 5 days per week. Motion discrimination and integration thresholds, Humphrey perimetry and structural and diffusion-weighted MRI were collected pre- and post-training. Changes in fractional anisotropy (FA) were analysed in visual tracts connecting the ipsilesional dorsal lateral geniculate nucleus and hMT+, and the ipsilesional dorsal lateral geniculate nucleus and primary visual cortex. The (non-visual) tract connecting the ventral posterior lateral nucleus of the thalamus and the primary somatosensory cortex was analysed as a control. Changes in white matter integrity were correlated with improvements in motion discrimination and Humphrey perimetry. We found that the magnitude of behavioural improvement was not directly related to changes in FA in the pathway between the dorsal lateral geniculate nucleus and hMT+ or dorsal lateral geniculate nucleus and primary visual cortex. Baseline FA in either tract also failed to predict improvements in training. However, an exploratory analysis showed a significant increase in FA in the distal part of the tract connecting the dorsal lateral geniculate nucleus and hMT+, suggesting that 6 months of visual training in chronic, retro-geniculate strokes may enhance white matter microstructural integrity of residual geniculo-extrastriate pathways.
The effect of ABM on attentional networks and stress-induced emotional reactivity in a mixed clinical sample with depression: A randomized sham-controlled trial
Research on the efficacy of Attention Bias Modification for depressive symptoms has predominantly yielded unfavorable outcomes. Despite adhering to rigorous conventions in randomized controlled trials, findings from these studies have indicated minimal effect sizes, thereby raising concerns about their limited clinical significance. This may be attributed to the overlapping mechanisms in ABM and the sham comparator, both affecting attentional processes. Participants with a diagnosis of major depressive disorder, with and without comorbid anxiety (N = 101) were randomized to a two-week preregistered randomized trial of ABM compared to sham. Attentional networks were assessed prior to and after the intervention by the Attention Network Task (ANT), and emotional reactivity was assessed in response to a lab-stressor. Irrespective of condition, participants improved their performance on the alerting and executive attentional networks, but not orienting, and stress-induced emotional reactivity was marginally decreased. Changes in attentional networks predicted post-intervention depression scores. It is imperative to reconsider the employment of a sham comparator in the exploration of the clinical efficacy of ABM.
The relationship between parameters and effects in transcranial ultrasonic stimulation.
Transcranial ultrasonic stimulation (TUS) is rapidly gaining traction for non-invasive human neuromodulation, with a pressing need to establish protocols that maximise neuromodulatory efficacy. In this review, we aggregate and examine empirical evidence for the relationship between tunable TUS parameters and in vitro and in vivo outcomes. Based on this multiscale approach, TUS researchers can make better informed decisions about optimal parameter settings. Importantly, we also discuss the challenges involved in extrapolating results from prior empirical work to future interventions, including the translation of protocols between models and the complex interaction between TUS protocols and the brain. A synthesis of the empirical evidence suggests that larger effects will be observed at lower frequencies within the sub-MHz range, higher intensities and pressures than commonly administered thus far, and longer pulses and pulse train durations. Nevertheless, we emphasise the need for cautious interpretation of empirical data from different experimental paradigms when basing protocols on prior work as we advance towards refined TUS parameters for human neuromodulation.