rudyvdbrink/CitationDatabase huggingface dataset:
Attention induced neural response trade-off in retinotopic cortex under load.
Scientific reports, 2016

The effects of perceptual load on visual cortex response to distractors are well established and various phenomena of 'inattentional blindness' associated with elimination of visual cortex response to unattended distractors, have been documented in tasks of high load. Here we tested an account for these effects in terms of a load-induced trade-off between target and distractor processing in retinotopic visual cortex. Participants were scanned using fMRI while performing a visual-search task and ignoring distractor checkerboards in the periphery. Retinotopic responses to target and distractors were assessed as a function of search load (comparing search set-sizes two, three and five). We found that increased load not only increased activity in frontoparietal network, but also had opposite effects on retinotopic responses to target and distractors. Target-related signals in areas V2-V3 linearly increased, while distractor response linearly decreased, with increased load. Critically, the slopes were equivalent for both load functions, thus demonstrating resource trade-off. Load effects were also found in displays with the same item number in the distractor hemisphere across different set sizes, thus ruling out local intrahemispheric interactions as the cause. Our findings provide new evidence for load theory proposals of attention resource sharing between target and distractor leading to inattentional blindness.
Survival in Parkinson's disease in relation to striatal dopamine transporter binding.
Parkinsonism & related disorders, 2017

To investigate whether dopamine transporter (DAT) binding, as measured with single photon emission computed tomography (SPECT), can be used to predict mortality in patients with Parkinson's disease (PD).
Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain.
Biological psychiatry, 2013

Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR.
Genome editing strategies: potential tools for eradicating HIV-1/AIDS.
Journal of neurovirology, 2015

Current therapy for controlling human immunodeficiency virus (HIV-1) infection and preventing acquired immunodeficiency syndrome (AIDS) progression has profoundly decreased viral replication in cells susceptible to HIV-1 infection, but it does not eliminate the low level of viral replication in latently infected cells, which contain integrated copies of HIV-1 proviral DNA. There is an urgent need for the development of HIV-1 genome eradication strategies that will lead to a permanent or "sterile" cure of HIV-1/AIDS. In the past few years, novel nuclease-initiated genome editing tools have been developing rapidly, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 system. These surgical knives, which can excise any genome, provide a great opportunity to eradicate the HIV-1 genome by targeting highly conserved regions of the HIV-1 long terminal repeats or essential viral genes. Given the time consuming and costly engineering of target-specific ZFNs and TALENs, the RNA-guided endonuclease Cas9 technology has emerged as a simpler and more versatile technology to allow permanent removal of integrated HIV-1 proviral DNA in eukaryotic cells, and hopefully animal models or human patients. The major unmet challenges of this approach at present include inefficient nuclease gene delivery, potential off-target cleavage, and cell-specific genome targeting. Nanoparticle or lentivirus-mediated delivery of next generation Cas9 technologies including nickase or RNA-guided FokI nuclease (RFN) will further improve the potential for genome editing to become a promising approach for curing HIV-1/AIDS.
A schizophrenia-associated HLA locus affects thalamus volume and asymmetry.
Brain, behavior, and immunity, 2015

Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia.
interferENZY: A Web-Based Tool for Enzymatic Assay Validation and Standardized Kinetic Analysis.
Journal of molecular biology, 2021

Enzymatic assays are widely employed to characterize important allosteric and enzyme modulation effects. The high sensitivity of these assays can represent a serious problem if the occurrence of experimental errors surreptitiously affects the reliability of enzyme kinetics results. We have addressed this problem and found that hidden assay interferences can be unveiled by the graphical representation of progress curves in modified reaction coordinates. To render this analysis accessible to users across all levels of expertise, we have developed a webserver, interferENZY, that allows (i) an unprecedented tight quality control of experimental data, (ii) the automated identification of small and major assay interferences, and (iii) the estimation of bias-free kinetic parameters. By eliminating the subjectivity factor in kinetic data reporting, interferENZY will contribute to solving the "reproducibility crisis" that currently challenges experimental molecular biology. The interferENZY webserver is freely available (no login required) at https://interferenzy.i3s.up.pt.
Narrative impairment, white matter damage and CSF biomarkers in the Alzheimer's disease spectrum.
Aging, 2019

Narrative discourse (ND) refers to one's ability to verbally reproduce a sequence of temporally and logically-linked events. Impairments in ND may occur in subjects with Amnestic Mild Cognitive Impairment (aMCI) and Alzheimer's Disease (AD), but correlates across this function, neuroimaging and cerebrospinal fluid (CSF) AD biomarkers remain understudied.
Pgc-1α and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina.
Investigative ophthalmology & visual science, 2015

The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors.
Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PARKIN-Deficient Human Dopamine Neurons.
Stem cell reports, 2020

Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role in the pathogenesis of Parkinson's disease (PD). PARKIN regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. Defects in mitophagy have been hypothesized to play a predominant role in the loss of dopamine (DA) neurons in PD. Here, we show that although there are defects in mitophagy in human DA neurons lacking PARKIN, the mitochondrial deficits are primarily due to defects in mitochondrial biogenesis that are driven by the upregulation of PARIS and the subsequent downregulation of PGC-1α. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without affecting the deficits in mitophagy. These results highlight the importance mitochondrial biogenesis versus mitophagy in the pathogenesis of PD due to inactivation or loss of PARKIN in human DA neurons.
Neuroscience and legal determination of criminal responsibility.
Nature reviews. Neuroscience, 2006

Neuroscience is increasingly identifying associations between biology and violence that appear to offer courts evidence relevant to criminal responsibility. In addition, in a policy era of 'zero tolerance of risk', evidence of biological abnormality in some of those who are violent, or biological markers of violence, may be seized on as a possible basis for preventive detention in the interest of public safety. However, there is a mismatch between questions that the courts and society wish answered and those that neuroscience is capable of answering. This poses a risk to the proper exercise of justice and to civil liberties.
Folic acid supplementation in pregnancy to prevent preterm birth: a systematic review and meta-analysis of randomized controlled trials.
European journal of obstetrics, gynecology, and reproductive biology, 2016

Folic acid (FA) may have a role in the prevention of pregnancy complications. However, the efficacy of FA supplementation in reducing the risk of preterm birth (PTB) is still unclear. The aim of this systematic review with meta-analysis was to evaluate the efficacy of folic acid supplementation during pregnancy to prevent preterm birth (PTB). The research protocol was designed a priori, defining methods for searching the literature in electronic databases, including and examining articles, and extracting and analyzing data. We included all randomized trials (RCTs) of asymptomatic singleton gestations without prior PTB who were randomized to prophylactic treatment with either FA supplementation or control (placebo or no treatment). The primary outcome was the incidence of PTB <37 weeks. Five randomized trials including 5,332 asymptomatic singleton gestations without prior PTB were included in the analysis. Women who received FA supplementation had a similar rate of PTB <37 weeks (22.6% vs 22.9%; RR 0.99, 95% CI 0.82-1.18), PTB<34 weeks (7.1% vs 8.7%; RR 0.77, 95% CI 0.55-1.09) and of preterm premature rupture of membranes (2.4% vs 2.9%; RR 0.81, 95% CI 0.44-1.50) compared with control group. Regarding neonatal outcome we found no significant differences in birth weight (mean difference 85.58g, 95% CI -55.17-226.34), low birth weight (21.0% vs 15.1%; RR 0.79, 95% CI 0.49 to 1.28) and perinatal death (2.9% vs 2.4%; RR 0.90, 95% CI 0.60-1.34). In summary, FA supplementation during pregnancy does not prevent PTB <37 weeks. Daily FA supplementation remains the most important intervention to reduce the risk of neural tube defects.
Configural processing in body posture recognition: an eye-tracking study.
Neuroreport, 2013

The body inversion effect is the finding that inverted body posture pictures are more difficult to recognize than upright body posture pictures are. The present study reinvestigated the body inversion effect in human observers using behavioral and eye movement measures to explore whether the body inversion effect correlates with specific eye movement features. Results showed that body postures elicited a robust and stable body inversion effect in reaction time throughout the experimental sessions. Eye-tracking data showed that the body inversion effect was robust only in the first fixation duration, but not in the second fixation duration. The analysis of the regions of interest showed that most fixations were located in the upper body for both the upright and the inverted body postures. Compared with inverted body postures, the upright postures led to a shorter reaction time and a shorter first fixation duration, but a larger portion of time to fixate on the head region, suggesting that participants tended to use head as a reference point to process upright body postures. For both the behavioral and the eye movement measures, the body inversion effect was robust for biomechanically possible body postures. However, for biomechanically impossible body postures (with angular manipulation of two joints), the effect was mixed. Although the error rate failed to show the body inversion effect, the reaction time measure and most eye movement measures, however, showed a body inversion effect. Overall, these results suggested that upright body postures are processed in expertise recognition and are processed configurally by human observers.
Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury.
Experimental neurology, 2021

Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with the partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-the corpus callosum and external capsules-based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and post-mitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.
Pathogenic Mechanisms and Therapy Development for C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2019

In 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of evidence favors gain of toxicity as the main pathogenic mechanism for C9orf72 repeat expansions. Alterations in several downstream cellular functions, such as nucleocytoplasmic transport and autophagy, are implicated. Exciting progress has also been made in therapy development targeting this mutation, such as by antisense oligonucleotide therapies targeting sense transcripts and small molecules targeting nucleocytoplasmic transport, and these are now in phase 1 clinical trials.
De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate.
Cell stem cell, 2018

DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.
Neurohormetic phytochemicals: An evolutionary-bioenergetic perspective.
Neurochemistry international, 2015

The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders.
A Bayesian spatial model for neuroimaging data based on biologically informed basis functions.
NeuroImage, 2017

The dominant approach to neuroimaging data analysis employs the voxel as the unit of computation. While convenient, voxels lack biological meaning and their size is arbitrarily determined by the resolution of the image. Here, we propose a multivariate spatial model in which neuroimaging data are characterised as a linearly weighted combination of multiscale basis functions which map onto underlying brain nuclei or networks or nuclei. In this model, the elementary building blocks are derived to reflect the functional anatomy of the brain during the resting state. This model is estimated using a Bayesian framework which accurately quantifies uncertainty and automatically finds the most accurate and parsimonious combination of basis functions describing the data. We demonstrate the utility of this framework by predicting quantitative SPECT images of striatal dopamine function and we compare a variety of basis sets including generic isotropic functions, anatomical representations of the striatum derived from structural MRI, and two different soft functional parcellations of the striatum derived from resting-state fMRI (rfMRI). We found that a combination of ∼50 multiscale functional basis functions accurately represented the striatal dopamine activity, and that functional basis functions derived from an advanced parcellation technique known as Instantaneous Connectivity Parcellation (ICP) provided the most parsimonious models of dopamine function. Importantly, functional basis functions derived from resting fMRI were more accurate than both structural and generic basis sets in representing dopamine function in the striatum for a fixed model order. We demonstrate the translational validity of our framework by constructing classification models for discriminating parkinsonian disorders and their subtypes. Here, we show that ICP approach is the only basis set that performs well across all comparisons and performs better overall than the classical voxel-based approach. This spatial model constitutes an elegant alternative to voxel-based approaches in neuroimaging studies; not only are their atoms biologically informed, they are also adaptive to high resolutions, represent high dimensions efficiently, and capture long-range spatial dependencies, which are important and challenging objectives for neuroimaging data.
Associations between serotonin transporter gene (SLC6A4) methylation and clinical characteristics and cortical thickness in children with ADHD.
Psychological medicine, 2015

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Additionally, environmental factors such as perinatal stress and early adversities contribute to the occurrence and severity of ADHD. Recently, DNA methylation has emerged as a mechanism that potentially mediates gene-environmental interaction effects in the aetiology and phenomenology of psychiatric disorders. Here, we investigated whether serotonin transporter gene (SLC6A4) methylation patterns were associated with clinical characteristics and regional cortical thickness in children with ADHD.