rudyvdbrink/CitationDatabase huggingface dataset:
A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing.
Molecular psychiatry, 2010

Neuropeptide S (NPS) is a recently discovered G protein-coupled receptor ligand that modulates fear-like behaviors in rodents. A frequent A>T single-nucleotide polymorphism in the human NPS receptor gene NPSR1 confers a 10-fold higher efficacy of NPS signaling in vitro and has been linked with panic disorder (PD). We here report data from a classical fear-conditioning paradigm in healthy normal volunteers, in which carriers of the NPSR1 T allele evaluated their fear reactions to conditioned stimuli (CSs) as more pronounced than AA homozygous participants, although they did not show elevated peripheral-physiological conditioned responses (skin conductance responses-SCRs). T carriers also exhibited stronger CS-evoked brain activity in the rostral dorsomedial prefrontal cortex (dmPFC), an area that supports the explicit, conscious appraisal of threat stimuli. By contrast, more caudally situated mid-dmPFC, which has previously been associated with the generation of SCRs, showed no elevated response. Moreover, rostral dmPFC activation was correlated with participants' fear evaluations, further strengthening the link of this activation to increased individual fear appraisal. Our data suggest a genetic and neuroanatomical substrate for catastrophizing overinterpretations of fear reactions and provide a mechanistic explanation for the association between the NPSR1 T allele and PD.
Quantifying the spatial extent of the corollary discharge benefit to transsaccadic visual perception.
Journal of neurophysiology, 2016

Extraretinal information, such as corollary discharge (CD), is hypothesized to help compensate for saccade-induced visual input disruptions. However, support for this hypothesis is largely for one-dimensional transsaccadic visual changes, with little comprehensive information on the spatial characteristics. Here we systematically mapped the two-dimensional extent of this compensation by quantifying the insensitivity to different displacement metrics. Human subjects made saccades to targets positioned at different amplitudes (4° or 8°) and directions (rightward, oblique, or upward). After the saccade the initial target disappeared and, after a blank period, reappeared at a shifted location-a collinear, diagonal, or orthogonal displacement. Subjects reported the perceived shift direction, and we determined the displacement detection based on the perceptual judgments. The two-dimensional insensitivity fields resulting from the perceptual thresholds had spatial features similar to the saccadic eye movement variability: 1) scaled with movement amplitude, 2) oriented (less sensitive to the change) along the saccade vector, and 3) approximately constant in shape when normalized by movement amplitude. In addition, comparing the postsaccadic perceptual estimate of the presaccadic target location to that based solely on the postsaccade visual error showed that overall the perceptual estimate was approximately 50% more accurate and 35% less variable than estimates based solely on this visual information. However, this relationship was not uniform: The benefit of extraretinal information was observed largely for displacements with a component parallel to the saccade vector. These results suggest a graded use of extraretinal information when forming the postsaccadic perceptual evaluation of transsaccadic environmental changes.
Cerebellar Lobulus Simplex and Crus I Differentially Represent Phase and Phase Difference of Prefrontal Cortical and Hippocampal Oscillations.
Cell reports, 2019

The cerebellum has long been implicated in tasks involving precise temporal control, especially in the coordination of movements. Here we asked whether the cerebellum represents temporal aspects of oscillatory neuronal activity, measured as instantaneous phase and difference between instantaneous phases of oscillations in two cerebral cortical areas involved in cognitive function. We simultaneously recorded Purkinje cell (PC) single-unit spike activity in cerebellar lobulus simplex (LS) and Crus I and local field potential (LFP) activity in the medial prefrontal cortex (mPFC) and dorsal hippocampus CA1 region (dCA1). Purkinje cells in cerebellar LS and Crus I differentially represented specific phases and phase differences of mPFC and dCA1 LFP oscillations in a frequency-specific manner, suggesting a site- and frequency-specific cerebellar representation of temporal aspects of neuronal oscillations in non-motor cerebral cortical areas. These findings suggest that cerebellar interactions with cerebral cortical areas involved in cognitive functions might involve temporal coordination of neuronal oscillations.
The placebo effect: From concepts to genes.
Neuroscience, 2015

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson's disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioral, neurobiological, and genetic influences on the placebo effect. Consistent with recent conceptualizations, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, and social cues are centrally integrated to change behaviors and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that have identified key brain regions and modulatory mechanisms underlying placebo effects using well-established behavioral paradigms. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioral, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximize treatment outcomes in clinical settings.
The effect of repeated remote ischemic postconditioning on infarct size in patients with an ischemic stroke (REPOST): study protocol for a randomized clinical trial.
Trials, 2019

Remote ischemic postconditioning (rIPostC) refers to the observation that repeated, short periods of ischemia protect remote areas against tissue damage during and after prolonged ischemia. Based on previous observations of a potential neuroprotective effect of rIPostC, the aim of this study is to evaluate whether repeated rIPostC after an ischemic stroke can reduce infarct size, which could be translated to an improvement in clinical outcomes.
Scaled subprofile modeling of resting state imaging data in Parkinson's disease: methodological issues.
NeuroImage, 2011

Consistent functional brain abnormalities in Parkinson's disease (PD) are difficult to pinpoint because differences from the normal state are often subtle. In this regard, the application of multivariate methods of analysis has been successful but not devoid of misinterpretation and controversy. The Scaled Subprofile Model (SSM), a principal components analysis (PCA)-based spatial covariance method, has yielded critical information regarding the characteristic abnormalities of functional brain organization that underlie PD and other neurodegenerative disorders. However, the relevance of disease-related spatial covariance patterns (metabolic brain networks) and the most effective methods for their derivation has been a subject of debate. We address these issues here and discuss the inherent advantages of proper application as well as the effects of the misapplication of this methodology. We show that ratio pre-normalization using the mean global metabolic rate (GMR) or regional values from a "reference" brain region (e.g. cerebellum) that may be required in univariate analytical approaches is obviated in SSM. We discuss deviations of the methodology that may yield erroneous or confounding factors.
Nutritional status, brain network organization, and general intelligence.
NeuroImage, 2017

The high energy demands of the brain underscore the importance of nutrition in maintaining brain health and further indicate that aspects of nutrition may optimize brain health, in turn enhancing cognitive performance. General intelligence represents a critical cognitive ability that has been well characterized by cognitive neuroscientists and psychologists alike, but the extent to which a driver of brain health, namely nutritional status, impacts the neural mechanisms that underlie general intelligence is not understood. This study therefore examined the relationship between the intrinsic connectivity networks supporting general intelligence and nutritional status, focusing on nutrients known to impact the metabolic processes that drive brain function. We measured general intelligence, favorable connective architecture of seven intrinsic connectivity networks, and seventeen plasma phospholipid monounsaturated and saturated fatty acids in a sample of 99 healthy, older adults. A mediation analysis was implemented to investigate the relationship between empirically derived patterns of fatty acids, general intelligence, and underlying intrinsic connectivity networks. The mediation analysis revealed that small world propensity within one intrinsic connectivity network supporting general intelligence, the dorsal attention network, was promoted by a pattern of monounsaturated fatty acids. These results suggest that the efficiency of functional organization within a core network underlying general intelligence is influenced by nutritional status. This report provides a novel connection between nutritional status and functional network efficiency, and further supports the promise and utility of functional connectivity metrics in studying the impact of nutrition on cognitive and brain health.
Expression of Terminal Effector Genes in Mammalian Neurons Is Maintained by a Dynamic Relay of Transient Enhancers.
Neuron, 2016

Generic spinal motor neuron identity is established by cooperative binding of programming transcription factors (TFs), Isl1 and Lhx3, to motor-neuron-specific enhancers. How expression of effector genes is maintained following downregulation of programming TFs in maturing neurons remains unknown. High-resolution exonuclease (ChIP-exo) mapping revealed that the majority of enhancers established by programming TFs are rapidly deactivated following Lhx3 downregulation in stem-cell-derived hypaxial motor neurons. Isl1 is released from nascent motor neuron enhancers and recruited to new enhancers bound by clusters of Onecut1 in maturing neurons. Synthetic enhancer reporter assays revealed that Isl1 operates as an integrator factor, translating the density of Lhx3 or Onecut1 binding sites into transient enhancer activity. Importantly, independent Isl1/Lhx3- and Isl1/Onecut1-bound enhancers contribute to sustained expression of motor neuron effector genes, demonstrating that outwardly stable expression of terminal effector genes in postmitotic neurons is controlled by a dynamic relay of stage-specific enhancers.
History-dependent variability in population dynamics during evidence accumulation in cortex.
Nature neuroscience, 2016

We studied how the posterior parietal cortex combines new information with ongoing activity dynamics as mice accumulate evidence during a virtual navigation task. Using new methods to analyze population activity on single trials, we found that activity transitioned rapidly between different sets of active neurons. Each event in a trial, whether an evidence cue or a behavioral choice, caused seconds-long modifications to the probabilities that govern how one activity pattern transitions to the next, forming a short-term memory. A sequence of evidence cues triggered a chain of these modifications resulting in a signal for accumulated evidence. Multiple distinguishable activity patterns were possible for the same accumulated evidence because representations of ongoing events were influenced by previous within- and across-trial events. Therefore, evidence accumulation need not require the explicit competition between groups of neurons, as in winner-take-all models, but could instead emerge implicitly from general dynamical properties that instantiate short-term memory.
Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents.
Neurobiology of disease, 2014

In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and IL-1β protein were time-dependently overexpressed in the rat hind paw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-α, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-1β in the spinal cord. Subdiaphragmatic vagotomy and the α7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1β. Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways.
cTBS delivered to the left somatosensory cortex changes its functional connectivity during rest.
NeuroImage, 2015

The primary somatosensory cortex (SI) plays a critical role in somatosensation as well as in action performance and social cognition. Although the SI has been a major target of experimental and clinical research using non-invasive transcranial magnetic stimulation (TMS), to date information on the effect of TMS over the SI on its resting-state functional connectivity is very scant. Here, we explored whether continuous theta burst stimulation (cTBS), a repetitive TMS protocol, administered over the SI can change the functional connectivity of the brain at rest, as measured using resting-state functional magnetic resonance imaging (rs-fMRI). In a randomized order on two different days we administered active TMS or sham TMS over the left SI. TMS was delivered off-line before scanning by means of cTBS. The target area was selected previously and individually for each subject as the part of the SI activated both when the participant executes and observes actions. Three analytical approaches, both theory driven (partial correlations and seed based whole brain regression) and more data driven (Independent Component Analysis), indicated a reduction in functional connectivity between the stimulated part of the SI and several brain regions functionally associated with the SI including the dorsal premotor cortex, the cerebellum, basal ganglia, and anterior cingulate cortex. These findings highlight the impact of cTBS delivered over the SI on its functional connectivity at rest. Our data may have implications for experimental and therapeutic applications of cTBS over the SI.
The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010

Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca(2+)) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K(+)) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca(2+)-dependent K(+) channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K(v)1 family of K(+) channels, possibly the K(v)1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K(+) channels and is a proconvulsant, use of selective K(v)1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia.
Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome.
Nature neuroscience, 2012

Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model, Fmr1 knockout (Fmr1(-/y)). In Fmr1(-/y) mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5-long Homer scaffolds and corrected several phenotypes in Fmr1(-/y) mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many Fmr1(-/y) phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of Fmr1. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.
Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.
The Lancet. Neurology, 2020

Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS.
Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis.
Archives of neurology, 2011

In a recent genome-wide transcriptional analysis, we identified a gene signature for multiple sclerosis (MS), which reverted back to normal during pregnancy. Reversion was particularly evident for 7 genes: SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1, most of which encode negative regulators of inflammation.
The Dual Function of the Polybasic Juxtamembrane Region of Syntaxin 1A in Clamping Spontaneous Release and Stimulating Ca
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018

The exact function of the polybasic juxtamembrane region (5RK) of the plasma membrane neuronal SNARE, syntaxin 1A (Syx), in vesicle exocytosis, although widely studied, is currently not clear. Here, we addressed the role of 5RK in Ca
The function of the hippocampus and middle temporal gyrus in forming new associations and concepts during the processing of novelty and usefulness features in creative designs.
NeuroImage, 2020

Creative thought relies on the reorganization of existing knowledge to generate novel and useful concepts. However, how these new concepts are formed, especially through the processing of novelty and usefulness (which are usually regarded as the key properties of creativity), is not clear. Taking familiar and useful (FU) objects/designs as the starting point or fundamental baseline, we modified them into novel and useless (NS) objects/designs or novel and useful (NU) ones (i.e., truly creative ones) to investigate how the features of novelty and usefulness are processed (processing of novelty: NU minus FU; processing of usefulness: NU minus NS). Specifically, we predicted that the creative integration of novelty and usefulness entails not only the formation of new associations, which could be critically mediated by the hippocampus and adjacent medial temporal lobe (MTL) areas, but also the formation of new concepts or categories, which is supported by the middle temporal gyrus (MTG). We found that both the MTL and the MTG were involved in the processing of novelty and usefulness. The MTG showed distinctive patterns of information processing, reflected by strengthened functional connectivity with the hippocampus to construct new concepts and strengthened functional connectivity with the executive control system to break the boundaries of old concepts. Additionally, participants' subjective evaluations of concept distance showed that the distance between the familiar concept (FU) and the successfully constructed concept (NU) was larger than that between the FU and the unsuccessfully constructed concept (NS), and this pattern was found to correspond to the patterns of their neural representations in the MTG. These findings demonstrate the critical mechanism by which new associations and concepts are formed during novelty and usefulness processing in creative design; this mechanism may be critically mediated by the hippocampus-MTG connection.