Neurogenetic Research Research Articles

Perspectives for the application of neurogenetic research in programming Neurorehabilitation.

Certain genetic variants underlie the proper functioning of the nervous system. They affect the nervous system in all aspects - molecular, systemic, cognitive, computational and sensorimotor. The greatest changes in the nervous system take place in the process of its maturation in the period of psychomotor development, as well as during neurorehabilitation, the task of which is to rebuild damaged neuronal pathways, e.g. by facilitating movement or training cognitive functions. Certain genetic polymorphisms affect the effectiveness of the processes of reconstruction or restoration of neural structures, which is clearly reflected in the effects of neurorehabilitation. This review presents the perspectives for the application of neurogenetic research in programming neurorehabilitation by determining the relationship of as many as 16 different genetic polymorphisms with specific functions of importance in rehabilitation. Thanks to this broad view, it may be possible to predict the effectiveness of rehabilitation on the basis of genetic testing, which would significantly contribute to the development of personalized medicine and to the optimal management of medical services in healthcare systems.

Simple Febrile Seizures: A Benign Phenomena?

AbstractFebrile seizures are one of the most common neurological causes of visits to the emergency room. This article is a review of the current literature concerning the evaluation and treatment of children with febrile seizures. Longitudinal prospective studies such as the FEBSTAT study (consequences of prolonged febrile seizures in childhood) have contributed to elucidate the long-term outcome of patients with prolonged febrile seizures. Neurogenetic research also demonstrated the role of genetic mutations (mainly voltage-gated ion channels) in the etiology of febrile seizures. Most febrile seizures are self-limited events with low risk of injury or evolution into status epilepticus or sudden death. However, the use of rectal diazepam as acute abortive treatment for febrile seizures lasting 5 minutes or longer has gained acceptance as a first-line home intervention. Most patients with febrile seizures do not require extensive investigations, but the treatment involves a customized plan. Efforts should be directed to educate caregivers about prognosis and management of potential recurrences. In selected cases, appropriate use of preventive antiseizure medication may be a consideration.

TRNA Metabolism and Neurodevelopmental Disorders.

tRNAs are short noncoding RNAs required for protein translation. The human genome includes more than 600 putative tRNA genes, many of which are considered redundant. tRNA transcripts are subject to tightly controlled, multistep maturation processes that lead to the removal of flanking sequences and the addition of nontemplated nucleotides. Furthermore, tRNAs are highly structured and posttranscriptionally modified. Together, these unique features have impeded the adoption of modern genomics and transcriptomics technologies for tRNA studies. Nevertheless, it has become apparent from human neurogenetic research that many tRNA biogenesis proteins cause brain abnormalities and other neurological disorders when mutated. The cerebral cortex, cerebellum, and peripheral nervous system show defects, impairment, and degeneration upon tRNA misregulation, suggesting that they are particularly sensitive to changes in tRNA expression or function. An integrated approach to identify tRNA species and contextually characterize tRNA function will be imperative to drive future tool development and novel therapeutic design for tRNA-associated disorders.

Epileptic Encephalopathies as Neurodegenerative Disorders.

The epileptic encephalopathies are severe and often treatment-resistant conditions that are associated with a progressive disturbance of brain function, resulting in a broad range of neurological and non-neurological comorbidities. The concept of epileptic encephalopathies entails that the encephalopathy aspect of the overall condition is primarily driven by the epileptic activity of the disease, which often manifests as specific and pathological features on the electroencephalogram. Genetic factors in epileptic encephalopathies are increasingly recognized. As of 2016, more than 30 genes have been securely implicated as causative genes for genetic epileptic encephalopathies. Even though the traditional concept of epileptic encephalopathies entails that the progressive disturbance of brain dysfunction is primarily due to the abnormal hypersynchronous activity that underlies the seizure disorders, this strict concept rarely holds true for patients with identified genetic etiologies. More commonly, an underlying genetic etiology is thought to predispose both to the neurodevelopmental comorbidities and to the seizure phenotype with a complex interaction between both. In this chapter, we will elucidate to what extent neurodegeneration rather than epilepsy-related regression is a feature of the common epileptic encephalopathies, drawing parallels between two relatively separate fields of neurogenetic research.

A gene−brain−cognition pathway for the effect of an Alzheimer׳s risk gene on working memory in young adults

Identifying pathways by which genetic Alzheimer׳s disease (AD) risk factors exert neurocognitive effects in young adults are essential for the effort to develop early interventions to forestall or prevent AD onset. Here, in a brain-imaging cohort of 59 young adults, we investigated effects of a variant within the clusterin (CLU) gene on working memory function and gray matter volume in cortical areas that support working memory. In addition, we investigated the extent to which effects of CLU genotype on working memory were independent of variation in the strongest AD risk factor gene apolipoprotein E (APOE). CLU is among the strongest genetic AD risk factors and, though it appears to share AD pathogenesis-related features with, APOE, it has been far less well studied. CLU genotype was associated with working memory performance in our study cohort. Notably, we found that variation in gray matter volume in a parietal region, previously implicated in maintenance of information for working memory, mediated the effect of CLU on working memory performance. APOE genotype did not affect working memory within our sample, and did not interact with CLU genotype. To our knowledge, this work represents the first evidence of a behavioral effect of CLU genotype in young people. In addition, this work identifies the first gene−brain−cognition mediation effect pathway for the transmission of the effect of an AD risk factor. Relative to conventional pairwise associations in cognitive neurogenetic research, gene−brain−cognition mediation modeling provides a more integrated understanding of how genetic effects transmit from gene to brain to cognitive function.

Tissue Border Enhancement by inversion recovery MRI at 7.0 Tesla.

This contribution presents a magnetic resonance imaging (MRI) acquisition technique named Tissue Border Enhancement (TBE), whose purpose is to produce images with enhanced visualization of borders between two tissues of interest without any post-processing. The technique is based on an inversion recovery sequence that employs an appropriate inversion time to produce images where the interface between two tissues of interest is hypo-intense; therefore, tissue borders are clearly represented by dark lines. This effect is achieved by setting imaging parameters such that two neighboring tissues of interest have magnetization with equal magnitude but opposite sign; therefore, the voxels containing a mixture of each tissue (that is, the tissue interface) possess minimal net signal. The technique was implemented on a 7.0 T MRI system. This approach can assist the definition of tissue borders, such as that between cortical gray matter and white matter; therefore, it could facilitate segmentation procedures, which are often challenging on ultra-high-field systems due to inhomogeneous radiofrequency distribution. TBE allows delineating the contours of structural abnormalities, and its capabilities were demonstrated with patients with focal cortical dysplasia, gray matter heterotopia, and polymicrogyria. This technique provides a new type of image contrast and has several possible applications in basic neuroscience, neurogenetic research, and clinical practice, as it could improve the detection power of MRI in the characterization of cortical malformations, enhance the contour of small anatomical structures of interest, and facilitate cortical segmentation.

Incentive Relativity: Gene-Environment Interactions

Reward loss experiences are among the main sources of emotional stress that humans face throughout their lives. In the animal laboratory, it has been repeatedly shown that the unexpected omission or devaluation of a reinforcer triggers a physiological, cognitive, and behavioral state called frustration. This state involves emotional mechanisms that resemble those unleashed by the presentation of other aversive stimuli, inducing similar stress responses through the activation of brain circuits involved in fear and anxiety. Although this hypothesis has been supported by behavioral, pharmacological, hormonal, and neurobiological evidence, only a few studies have focused on the neurogenetic basis of frustration in animals. This review focuses on the gene-environment interactions that determine the emotional response under conditions of reward loss. Behavioral and genetic correlates of frustration are reviewed in two strains of animals selected on the basis of extreme differences in active avoidance learning: inbred Roman High- (RHA-I) and Roman Low-Avoidance (RLA-I) rats. The review shows the usefulness of Roman strains for neurogenetic research and sets out unsolved questions regarding gene-environment interactions underlying behavior induced by incentive loss.

Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms

In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the "Brain Reward Cascade" (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications.

Recent advances in clinical neurogenetics

Herein, I review the main papers in neurogenetic research published in the Journal of Neurology over the last year.

Learning about prospective mates in male fruit flies: effects of acceptance and rejection

Neurogenetic research in fruit flies (Drosophila melanogaster) has established numerous protocols that illustrate flies' rich behavioural repertoire as well as excellent learning and memory abilities. To place that information in an evolutionary context, we followed up on earlier studies by evaluating the effect of experience with a variety of relevant female categories on males' courtship behaviour. We found, for the first time, that the experience of mating with conspecific females caused males to subsequently show lower levels of courtship towards heterospecific females compared to control males. These courtship levels, however, were higher than those of males that had experienced rejection by heterospecific females. Courtship reduction was selective: males that mated conspecifically did not subsequently show low levels of courting other conspecific females, and males that were rejected by recently mated conspecific females did not show low levels of courting heterospecific females. Interestingly, males that mated with virgin conspecifics and males that were rejected by virgin heterospecifics subsequently showed similar levels of low courtship towards recently mated conspecific females, suggesting that males find mated females unattractive after encountering virgin females. Males, however, showed higher levels of courtship towards mated females after mating with simulated mated females than after mating with control virgin females. Overall, our results indicate that adaptive use of learning by male fruit flies enhances mating success and reduces time and effort pursuing relatively less desirable or attainable females.

Analysis of cell identity, morphology, apoptosis and mitotic activity in a primary neural cell culture system in Drosophila

In Drosophila, most neurogenetic research is carried out in vivo. Mammalian research demonstrates that primary cell culture techniques provide a powerful model to address cell autonomous and non-autonomous processes outside their endogenous environment. We developed a cell culture system in Drosophila using wildtype and genetically manipulated primary neural tissue for long-term observations. We assessed the molecular identity of distinct neural cell types by immunolabeling and genetically expressed fluorescent cell markers. We monitored mitotic activity of cell cultures derived from wildtype and tumorous larval brains. Our system provides a powerful approach to unveil developmental processes in the nervous system and to complement studies in vivo.

Healthy brain ageing: the new concept of motivational reserve

SummaryVarious research approaches try to solve the puzzles related to dementia or healthy brain ageing. Neurogenetic, neuroimaging and neuropharmacological research are the most visible of these. Psychological research in dementia has been instrumental in improving familial or institutional care. However, it has not been regarded as basic research. Recent psychological research into the mechanisms of co-forming or shaping the clinical presentation of dementias can be counted as truly basic research. The ‘cognitive or brain reserve’ concept has been fruitful in implementing psychological knowledge on plasticity factors in dementia. The new concept of ‘motivational reserve capacity’ extends these psychological concepts. In particular, it provides a basis for integrating various findings on how lifestyle factors effectively shape clinical dementia presentations – or lead to healthy brain ageing.

The Ever Expanding Spinocerebellar Ataxias. Editorial

The spinocerebellar ataxias (SCAs) are a clinically, genetically, and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and non-cerebellar symptoms that, in many cases,defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its relay connexions. The current identification of at least 43 SCA subtypes and the causative molecular defects in 27 of them refine the clinical diagnosis,provide molecular testing of at risk, a/pre-symptomatic, prenatal or pre-implantation and facilitate genetic counselling. The recent discovery of new causative SCA genes along with the respective scientific advances is uncovering high complexity and altered molecular pathways involved in the mechanisms by which the mutant gene products cause pathogenesis. Fortunately, the intensive ongoing clinical and neurogenetic research together with the applied molecular approaches is sure to yield scientific advances that will be translated into developing effective treatments for the spinocerebellar ataxias and other similar neurological conditions.

A Gene–Brain–Cognition Pathway: Prefrontal Activity Mediates the Effect of COMT on Cognitive Control and IQ

A core thesis of cognitive neurogenetic research is that genetic effects on cognitive ability are mediated by specific neural functions, however, demonstrating neural mediation has proved elusive. Pairwise relationships between genetic variation and brain function have yielded heterogeneous findings to date. This heterogeneity indicates that a multiple mediator modeling approach may be useful to account for complex relationships involving function at multiple brain regions. This is relevant not only for characterizing healthy cognition but for modeling the complex neural pathways by which disease-related genetic effects are transmitted to disordered cognitive phenotypes in psychiatric illness. Here, in 160 genotyped functional magnetic resonance imaging participants, we used a multiple mediator model to test a gene-brain-cognition pathway by which activity in 4 prefrontal brain regions mediates the effects of catechol-O-methyltransferase (COMT) gene on cognitive control and IQ. Results provide evidence for gene-brain-cognition mediation and help delineate a pathway by which gene expression contributes to intelligence.

How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: On defining and measuring psychological phenotypes in neurogenetic research.

The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

Tangles of Neurogenetics, Neuroethics, and Culture

Neurogenetics promises rich insights into how the mind works. Researchers investigating the range of topics from normal brain functioning to pathological states are increasingly looking to genetics for clues on human variability and disease etiology. Is it fair to assume this interest in neurogenetics is universal? How should researchers and clinicians approach ideas of consent to research or prediction of disease when a subject or patient understands the mind with concepts or language incompatible with neurogenetics? In this paper we consider how non-Western philosophies bring complexity to ideas of individual and community consent and confidentiality in the context of neurogenetics.

The role of comorbidity in delineating the etiopatomechanism of disease: the co-occurrence of migraine with aura and restless leg syndrome

Background The etiology and patomachanism of migraine is not yet fully understood. This may be related to the fact that the eitopathology of disorders comorbid with migraine (depression, restless leg syndrome) is also not fully known. The common well-known syndromes of migraine attack include nausea, vomiting, drowsiness, and its comorbidity with restless leg syndrome (RLS) and related neurogenetic and neurochemical research in the past years led to the proposal of the pathogenetic role of the dopaminergic system in the development of migraine. RLS affects about 10-15% of USA population and shows a 17% comorbidity with migraine. RLS is a sensomotor disorder showing a circadian pattern which worsens in a quiet awake state (especially around falling asleep). Often a permanent sleep-wake disorder develops with mental and affective disturbances. The origin of RLS is idiopathic in 30-40% of cases but it can also be familiar. In the background of secunder RLS there is often iron deficiency periferal neuropahty, uraemia, rheumatoid arthiritis, diabetes, etc is present. Pregnancy and hormonal symptoms may also enhance the symptoms. The treatment is complex: pharmacological and non-pharmacological therapy. We would like to present the case of a 57 year old woman who suffers from migraine with visual aura since her young adulthood and from restless leg syndrome since the age of 48, together with relevant literature data. She sought medical and psychological help for her sleep-wake disturbances, affective symptoms and deterioriating quality of life present in the last few years. Author details Department of Clinical Psychology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. Department of Clinical and Theoretical Mental Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.

The Neuroterrain 3D Mouse Brain Atlas.

A significant objective of neuroinformatics is the construction of tools to readily access, search, and analyze anatomical imagery. This goal can be subdivided into development of the necessary databases and of the computer vision tools for image analysis. When considering mesoscale images, the latter tools can be further divided into registration algorithms and anatomical models. The models are atlases that contain both bitmap images and templates of anatomical boundaries. We report here on construction of such a model for the C57BL/6J mouse. The intended purpose of this atlas is to aid in automated delineation of the Mouse Brain Library, a database of brain histological images of importance to neurogenetic research.

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FROM DISABLING TO ENABLING THE PUBLIC INTEREST: NATURAL TRANSITIONS FROM GAMBLING EXPOSURE TO ADAPTATION AND SELF‐REGULATION

FROM DISABLING TO ENABLING THE PUBLIC INTEREST: NATURAL TRANSITIONS FROM GAMBLING EXPOSURE TO ADAPTATION AND SELF‐REGULATION