rudyvdbrink/CitationDatabase huggingface dataset:
Genetic interactions with stressful environments in depression and addiction.
BJPsych advances, 2021

Stress is the most important proximal precipitant of depression, yet most large genome-wide association studies (GWAS) do not include stress as a variable. Here, we review how gene × environment (G × E) interaction might impede the discovery of genetic factors, discuss two examples of G × E interaction in depression and addiction, studies incorporating high-stress environments, as well as upcoming waves of genome-wide environment interaction studies (GWEIS). We discuss recent studies which have shown that genetic distributions can be affected by social factors such as migrations and socioeconomic background. These distinctions are not just academic but have practical consequences. Owing to interaction with the environment, genetic predispositions to depression should not be viewed as unmodifiable destiny. Patients may genetically differ not just in their response to drugs, as in the now well-recognised field of pharmacogenetics, but also in how they react to stressful environments and how they are affected by behavioural therapies.
Complexity of brain activity and connectivity in functional neuroimaging.
Journal of neuroscience research, 2018

Understanding the complexity of human brain dynamics and brain connectivity across the repertoire of functional neuroimaging and various conditions, is of paramount importance. Novel measures should be designed tailored to the input focusing on multichannel activity and dynamic functional brain connectivity (DFBC). Here, we defined a novel complexity index (CI) from the field of symbolic dynamics that quantifies patterns of different words up to a length from a symbolic sequence. The CI characterizes the complexity of the brain activity. We analysed DFBC by adopting the sliding window approach using imaginary part of phase locking value (iPLV) for EEG/ECoG/MEG and wavelet coherence (WC) for fMRI. Both intra and cross-frequency couplings (CFC) namely phase-to-amplitude were estimated using iPLV/WC at every snapshot of the DFBC. Using proper surrogate analysis, we defined the dominant intrinsic coupling mode (DICM) per pair of regions-of-interest (ROI). The spatiotemporal probability distribution of DICM were reported to reveal the most prominent coupling modes per condition and modality. Finally, a novel flexibility index is defined that quantifies the transition of DICM per pair of ROIs between consecutive time windows. The whole methodology was demonstrated using four neuroimaging datasets (EEG/ECoG/MEG/fMRI). Finally, we succeeded to totally discriminate healthy controls from schizophrenic using FI and dynamic reconfiguration of DICM. Anaesthesia independently of the drug caused a global decreased of complexity in all frequency bands with the exception in δ and alters the dynamic reconfiguration of DICM. CI and DICM of MEG/fMRI resting-state recordings in two spatial scales were high reliable.
Social Order: Using The Sequential Structure of Social Interaction to Discriminate Abnormal Social Behavior in the Rat.
Learning and motivation, 2018

Social interactions form the basis of a broad range of functions related to survival and mating. The complexity of social behaviors and the flexibility required for normal social interactions make social behavior particularly susceptible to disruption. The consequences of developmental insults in the social domain and the associated neurobiological factors are commonly studied in rodents. Though methods for investigating social interactions in the laboratory are diverse, animals are typically placed together in an apparatus for a brief period (under 30 min) and allowed to interact freely while behavior is recorded for subsequent analysis. A standard approach to the analysis of social behavior involves quantification of the frequency and duration of individual social behaviors. This approach provides information about the allocation of time to particular behaviors within a session, which is typically sufficient for detection of robust alterations in behavior. Virtually all social species, however, display complex sequences of social behavior that are not captured in the quantification of individual behaviors. Sequences of behavior may provide more sensitive indicators of disruptions in social behavior. Sophisticated analysis systems for quantification of behavior sequences have been available for many years; however, the required training and time to complete these analyses represent significant barriers to high-throughput assessments. We present a simple approach to the quantification of behavioral sequences that requires minimal additional analytical steps after individual behaviors are coded. We implement this approach to identify altered social behavior in rats exposed to alcohol during prenatal development, and show that the frequency of several pairwise sequences of behavior discriminate controls from ethanol-exposed rats when the frequency of individual behaviors involved in those sequences does not. Thus, the approach described here may be useful in detecting subtle deficits in the social domain and identifying neural circuits involved in the organization of social behavior.
Glucocorticoids and cortical decoding in the phobic brain.
Psychiatry research. Neuroimaging, 2020

Glucocorticoids reduce phobic fear in anxiety disorders and enhance psychotherapy, possibly by reducing the retrieval of fear memories and enhancing the consolidation of new corrective memories. Glucocorticoid signaling in the basolateral amygdala can influence connected fear and memory-related cortical regions, but this is not fully understood. Previous studies investigated specific pathways moderated by glucocorticoids, for example, visual-temporal pathways; however, these analyses were limited to a-priori selected regions. Here, we performed whole-brain pattern analysis to localize phobic stimulus decoding related to the fear-reducing effect of glucocorticoids. We reanalyzed functional magnetic resonance imaging (fMRI) data from a previously published study with spider-phobic patients and healthy controls. The patients received glucocorticoids or a placebo before the exposure to spider images. There was moderate evidence that patients with phobia had higher decoding of phobic content in the anterior cingulate cortex (ACC) and the left and right anterior insula compared to controls. Decoding in the ACC and the right insula showed strong evidence for correlation with experienced fear. Patients with cortisol reported a reduction of fear by 10-13%; however, there was only weak evidence for changes in neural decoding compared to placebo which was found in the precuneus, the opercular cortex, and the left cerebellum.
The sequestration of hydroxyapatite nanoparticles by human monocyte-macrophages in a compartment that allows free diffusion with the extracellular environment.
Biomaterials, 2011

Calcium phosphate and hydroxyapatite nanoparticles are extensively researched for medical applications, including bone implant materials, DNA and SiRNA delivery vectors and slow release vaccines. Elucidating the mechanisms by which cells internalize nanoparticles is fundamental for their long-term exploitation. In this study, we demonstrate that hydrophilic hydroxyapatite nanoparticles are sequestered within a specialized compartment called SCC (surface-connected compartment). This membrane-bound compartment is an elaborate labyrinth-like structure directly connected to the extracellular space. This continuity is demonstrated by in vivo 2-photon microscopy of ionic calcium using both cell-permeable and cell-impermeable dyes and by 3-D reconstructions from serial block-face SEM of fixed cells. Previously, this compartment was thought to be initiated specifically by exposure of macrophages to hydrophobic nanoparticles. However, we show that the SCC can be triggered by a much wider range of nanoparticles. Furthermore, we demonstrate its formation in A549 human lung epithelial cells, which are considerably less phagocytic than macrophages. EDX shows that extensive amounts of hydroxyapatite nanoparticles can be sequestered in this manner. We propose that SCC formation may be a means to remove large amounts of foreign material from the extracellular space, followed by slow degradation, may be to avoid excessive damage to surrounding cells or tissues.
Extent of Single-Neuron Activity Modulation by Hippocampal Interictal Discharges Predicts Declarative Memory Disruption in Humans.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020

Memory deficits are common in epilepsy patients. In these patients, the interictal EEG commonly shows interictal epileptiform discharges (IEDs). While IEDs are associated with transient cognitive impairments, it remains poorly understood why this is. We investigated the effects of human (male and female) hippocampal IEDs on single-neuron activity during a memory task in patients with medically refractory epilepsy undergoing depth electrode monitoring. We quantified the effects of hippocampal IEDs on single-neuron activity and the impact of this modulation on subjectively declared memory strength. Across all recorded neurons, the activity of 50 of 728 neurons were significantly modulated by IEDs, with the strongest modulation in the medial temporal lobe (33 of 416) and in particular the right hippocampus (12 of 58). Putative inhibitory neurons, as identified by their extracellular signature, were more likely to be modulated by IEDs than putative excitatory neurons (19 of 157 vs 31 of 571). Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption of recognition of familiar images only if they occurred up to 2 s before stimulus onset. In contrast, IEDs did not impair encoding or recognition of novel images, indicating high temporal and task specificity of the effects of IEDs. The degree of modulation of individual neurons by an IED correlated with the declared confidence of a retrieval trial, with higher firing rates indicative of reduced confidence. Together, these data link the transient modulation of individual neurons by IEDs to specific declarative memory deficits in specific cell types, thereby revealing a mechanism by which IEDs disrupt medial temporal lobe-dependent declarative memory retrieval processes.
Changes in corticospinal excitability evoked by common peroneal nerve stimulation depend on stimulation frequency.
Experimental brain research, 2010

The afferent volley generated during neuromuscular electrical stimulation (NMES) can increase the excitability of the human corticospinal (CS) pathway. This study was designed to determine the effect of different frequencies of NMES applied over the common peroneal nerve on changes in CS excitability for the tibialis anterior (TA) muscle. We hypothesized that higher frequencies of stimulation would produce larger increases in CS excitability than lower frequencies. NMES was applied at 10, 50, 100, or 200 Hz during separate sessions held at least 48 h apart. The stimulation was delivered in a 20 s on, 20 s off cycle for 40 min using a 1 ms pulse width. The intensity of stimulation was set to evoke an M-wave in response to a single pulse that was 15% of the maximal M-wave. CS excitability was evaluated by the amplitude of motor-evoked potentials (MEPs) in TA evoked by transcranial magnetic stimulation. MEPs were recorded immediately before and after the 40 min of NMES and in each 20 s "off" period. For each subject, MEPs recorded during three successive "off" periods were averaged together (n = 9 MEPs), providing a temporal resolution of 2 min for assessing changes in CS excitability. When delivering NMES at 100 Hz, MEPs became significantly elevated from those evoked before the stimulation at the 24th min, and there was a twofold increase in MEP amplitude after 40 min. NMES delivered at 10, 50, and 200 Hz did not significantly alter MEP amplitude. The amplitude of MEPs evoked in soleus and vastus medialis followed similar patterns as those evoked simultaneously in TA, but these changes were mostly not of statistical significance. There were no changes in the ratio of maximal H-reflex to maximal M-wave in TA or soleus. These experiments demonstrate a frequency-dependent effect of NMES on CS excitability for TA and show that, under the conditions of the present study, 100-Hz stimulation was more effective than 10, 50, and 200 Hz. This effect of NMES on CS excitability was strongest in the stimulated muscle and may be mediated primarily at a supraspinal level. These results contribute to a growing body of knowledge about how the afferent volley generated during NMES influences the CNS and have implications for identifying optimal NMES parameters to augment CS excitability for rehabilitation of dorsiflexion after CNS injury.
Identification of Immunoreactive Luteinizing Hormone Receptors in the Adrenal Cortex of the Female Rhesus Macaque.
Reproductive sciences (Thousand Oaks, Calif.), 2016

Female laboratory macaques were studied under a variety of treatment protocols to determine if immunoreactive luteinizing hormone/gonadal chorionic gonadotropin (LH/CG) receptors were present in the adrenal cortex. All adrenal tissues revealed an absence of immunoreactivity in the in the medulla while staining was present in all three outer zones of the cortex. Increased staining was observed in the zonae reticularis with least staining in the zonae glomerulosa. Moderate and variable staining was found in the zonae fasciculata. These results demonstrate that LH/CG receptors in the adrenal cortex may be more common in higher primates than previously recognized and help explain some aspects of the endocrine changes observed in mid-aged women during the menopausal transition when circulating LH concentrations are rising.
Both thalamic and pallidal deep brain stimulation for myoclonic dystonia.
Journal of neurosurgery, 2010

Myoclonic dystonia is poorly managed with medication and may be severe enough to warrant surgical intervention. Surgery has targeted either the globus pallidus pars interna (GPi) or the thalamus, but there is no accepted target for this condition. The authors present the case of a 23-year-old man treated with unilateral deep brain stimulation in both the thalamus and GPi. His movement disorder improved dramatically with stimulation. Two years postoperatively, the authors performed a double-blind assessment of the effects of each stimulator together, separately, and off stimulation. Videotape assessment, using tremor, dystonia, and myoclonus rating scales, showed that most of the benefit could be attributed to pallidal stimulation, although there was some advantage to stimulation at both sites. These results suggest that while GPi stimulation may be the better target for this condition, thalamic stimulation may be added in cases in which the benefit is insufficient.
Physiological consequences of repeated exposures to conditioned fear.
Behavioral sciences (Basel, Switzerland), 2012

Activation of the stress response evokes a cascade of physiological reactions that may be detrimental when repeated or chronic, and when triggered after exposure to psychological/emotional stressors. Investigation of the physiological mechanisms responsible for the health damaging effects requires animal paradigms that repeatedly evoke a response to psychological/emotional stressors. To this end, adult male Sprague Dawley rats were repeatedly exposed (2X per day for 20 days) to a context that they were conditioned to fear (conditioned fear test, CFT). Repeated exposure to CFT produced body weight loss, adrenal hypertrophy, thymic involution, and basal corticosterone elevation. In vivo biotelemetry measures revealed that CFT evokes sympathetic nervous system driven increases in heart rate (HR), mean arterial pressure (MAP), and core body temperature. Extinction of behavioral (freezing) and physiological responses to CFT was prevented using minimal reinstatement footshock. MAP responses to the CFT did not diminish across 20 days of exposure. In contrast, HR and cardiac contractility responses declined by day 15, suggesting a shift toward vascular-dominated MAP (a pre-clinical marker of CV dysfunction). Flattened diurnal rhythms, common to stress-related mood/anxiety disorders, were found for most physiological measures. Thus, repeated CFT produces adaptations indicative of the health damaging effects of psychological/emotional stress.
Excitability changes related to GABAA receptor plasticity during pregnancy.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

Alterations in GABA(A) receptor (GABA(A)R) expression and function, similar to those we described previously during pregnancy in the mouse dentate gyrus, may also occur in other brain regions. Here we show, using immunohistochemical techniques, a decreased delta subunit-containing GABA(A)R (deltaGABA(A)R) expression in the dentate gyrus, hippocampal CA1 region, thalamus, and striatum but not in the cerebral cortex. In the face of the highly elevated neurosteroid levels during pregnancy, which can act on deltaGABA(A)Rs, it may be beneficial to decrease the number of neurosteroid-sensitive receptors to maintain a steady-state level of neuronal excitability throughout pregnancy. Consistent with this hypothesis, the synaptic input/output (I/O) relationship in the dentate gyrus molecular layer in response to lateral perforant path stimulation was shifted to the left in hippocampal slices from pregnant compared with virgin mice. The addition of allopregnanolone, at levels comparable with those found during pregnancy (100 nM), shifted the I/O curves in pregnant mice back to virgin levels. There was a decreased threshold to induce epileptiform local field potentials in slices from pregnant mice compared with virgin, but allopregnanolone reverted the threshold for inducing epileptiform activity to virgin levels. According to these data, neuronal excitability is increased in pregnant mice in the absence of allopregnanolone attributable to brain region-specific downregulation of deltaGABA(A)R expression. In brain regions, such as the cortex, that do not exhibit alterations in deltaGABA(A)R expression, there were no changes in the I/O relationship during pregnancy. Similarly, no changes in network excitability were detected in pregnant Gabrd(-/-) mice that lack deltaGABA(A)Rs, suggesting that changes in neuronal excitability during pregnancy are attributable to alterations in the expression of these receptors. Our findings indicate that alterations in deltaGABA(A)R expression during pregnancy result in brain region-specific increases in neuronal excitability that are restored by the high levels of allopregnanolone under normal conditions but under pathological conditions may result in neurological and psychiatric disorders associated with pregnancy and postpartum.
A porcine model of neurofibromatosis type 1 that mimics the human disease.
JCI insight, 2018

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1+/ex42del miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.
Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
Pediatrics, 2020

There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.
The 
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017

The protein family of degenerin/epithelial sodium channels (DEG/ENaCs) is composed of diverse animal-specific, non-voltage-gated ion channels that play important roles in regulating cationic gradients across epithelial barriers. Some family members are also enriched in neural tissues in both vertebrates and invertebrates. However, the specific neurophysiological functions of most DEG/ENaC-encoding genes remain poorly understood. The fruit fly
Integrated Functional Analysis Implicates Syndromic and Rare Copy Number Variation Genes as Prominent Molecular Players in Pathogenesis of Autism Spectrum Disorders.
Neuroscience, 2020

Autism Spectrum Disorders (ASD) are caused by disrupted neurodevelopment leading to socio-communication and behavioural abnormalities. Although genetic anomalies like Copy Number Variations (CNV) have been implicated in ASD, their overall genomic landscape and pathogenicity remain elusive. Therefore, we created a CNV map for ASD using 9337 cases and 5650 controls from SFARI database, statistically marked genomic regions with high and low frequencies of CNVs (i.e., common and rare CNV regions respectively), performed gene function enrichment for CNV genes, built functional networks, pathways and examined their expression in brain tissues. Information thus obtained were cumulatively integrated using a weighted scoring strategy to rank CNV regions by their neuro-functional attributes. Subsequently, we mapped 105 genic CNV regions across 20 chromosomes. They encompassed 537 genes, of which only 59 (11%) genes were identified with Single Nucleotide Variations (SNV) in ASD subjects through sequencing and functional studies, which indicated that diverse sets of genes were affected by CNVs and SNVs in ASD. Overall, syndromic CNV regions displayed the most prominent neuronal functions. While common CNV regions were found in loci 15q11.2, 16p11.2, 22q11.21, 15q13.2-13.3, rare CNV regions in loci 4p16.3, 9q34.3, 7q11.23, 17p11.2 contributed significantly to protein interaction networks and were highly expressed in brain. Enriched CNV genes were clustered in six functional categories with either direct roles in neurodevelopment or auxiliary roles like cellular signalling via MAPK pathway, cytoskeletal organization and transport or immune regulation. Mechanisms through which these molecular systems could independently or in combination trigger an ASD phenotype were predicted.