| 1. |
- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 2. |
- Fenstermacher, M.E., et al.
(author)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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In: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Journal article (peer-reviewed)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 3. |
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| 4. |
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| 5. |
- Kempermann, G., et al.
(author)
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Human Adult Neurogenesis: Evidence and Remaining Questions
- 2018
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In: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 23:1, s. 25-30
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Journal article (peer-reviewed)abstract
- Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.
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| 6. |
- Kurz, Alexander, et al.
(author)
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RHAPSODY - Internet-based support for caregivers of people with young onset dementia : program design and methods of a pilot study
- 2016
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In: International psychogeriatrics. - 1041-6102 .- 1741-203X. ; 28:12, s. 2091-2099
-
Journal article (peer-reviewed)abstract
- Background: Young Onset Dementia (YOD), defined by first symptoms of cognitive or behavioral decline occurring before the age of 65 years, is relatively rare compared to dementia of later onset, but it is associated with diagnostic difficulty and heavy burden on affected individuals and their informal carers. Existing health and social care structures rarely meet the needs of YOD patients. Internet-based interventions are a novel format of delivering health-related education, counseling, and support to this vulnerable yet underserved group. Methods: The RHAPSODY (Research to Assess Policies and Strategies for Dementia in the Young) project is a European initiative to improve care for people with YOD by providing an internet-based information and skill-building program for family carers. The e-learning program focuses on managing problem behaviors, dealing with role change, obtaining support, and looking after oneself. It will be evaluated in a pilot study in three countries using a randomized unblinded design with a wait-list control group. Participants will be informal carers of people with dementia in Alzheimer's disease or behavioral-variant Frontotemporal degeneration with an onset before the age of 65 years. The primary outcome will be caregiving self-efficacy after 6 weeks of program use. As secondary outcomes, caregivers' stress and burden, carer health-related quality of life, caring-related knowledge, patient problem behaviors, and user satisfaction will be assessed. Program utilization will be monitored and a health-economic evaluation will also be performed. Conclusions: The RHAPSODY project will add to the evidence on the potential and limitations of a conveniently accessible, user-friendly, and comprehensive internet-based intervention as an alternative for traditional forms of counseling and support in healthcare, aiming to optimize care and support for people with YOD and their informal caregivers.
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| 7. |
- Bhardwaj, R. D., et al.
(author)
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Neocortical neurogenesis in humans is restricted to development.
- 2006
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 103:33, s. 12564-8
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Journal article (peer-reviewed)abstract
- Stem cells generate neurons in discrete regions in the postnatal mammalian brain. However, the extent of neurogenesis in the adult human brain has been difficult to establish. We have taken advantage of the integration of (14)C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral neocortex. Together with the analysis of the neocortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that, whereas nonneuronal cells turn over, neurons in the human cerebral neocortex are not generated in adulthood at detectable levels but are generated perinatally.
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| 8. |
- Bigdeli, TB, et al.
(author)
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Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry
- 2020
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In: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 25:10, s. 2455-2467
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Journal article (peer-reviewed)abstract
- Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.
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| 9. |
- Björklund, Anders, et al.
(author)
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Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation.
- 1983
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In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 1-7
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Journal article (peer-reviewed)abstract
- The steps involved in the grafting of mesencephalic and septal embryonic tissue in the form of dissociated cell suspensions are described in detail. This includes dissection of the donor embryos, incubation in trypsin, mechanical dissociation, and stereotaxic injection into the brains of adult recipient rats. Some of the technical problems and limitations are discussed.
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| 10. |
- Björklund, Anders, et al.
(author)
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Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cells implanted in different brain sites
- 1983
-
In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 9-18
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Journal article (peer-reviewed)abstract
- Dissociated dopamine-rich cell suspensions were prepared from the ventral mesencephalon of rat embryos and injected in one or several sites in striatal and non-striatal regions in the dopaminergically denervated brain of adult rats. While the grafts survived well in all sites, the dopamine fibre outgrowth was markedly different depending on whether the grafts occurred in an area normally innervated by the mesencephalic dopamine neurones (i.e. neostriatum or nc. accumbens) or in areas not normally innervated by these neurones (i.e. parietal cortex, lateral hypothalamus or substantia nigra). Moreover, in grafts placed at different sites along the trajectory of the nigrostriatal pathway the outgrowing fibres remained confined to the graft, and there was little evidence that the implanted neurones could elongate their axons along the pathway of the nigrostriatal tract to reach the striatum from a distance. Thus, the intracerebral suspension grafts provided efficient reinnervation of a denervated target only when placed in the immediate vicinity of the target area. The results of multiple graft placements indicate that a relatively complete restoration of a lost innervation should be possible to achieve in large areas of the brain, such as the striatal complex, with the suspension grafting technique.
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| 11. |
- Björklund, Anders, et al.
(author)
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Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippccampus reinnervated by septal suspension implants
- 1983
-
In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 59-66
-
Journal article (peer-reviewed)abstract
- The time-course and magnitude of fibre outgrowth from septal suspension grafts injected into the previously denervated hippocampal formation was monitored by measurements of choline acetyltransferase (ChAT), and the activity of the grafted neurons was assessed by measurements of [14C]acetylcholine (ACh) synthesis from [14C]glucose in vitro. Graft-derived ChAT activity was barely detectable 10 days after grafting, but increased sharply between 10 days and 1 month in the areas of the hippocampus located close to the septal implants. By 6 months ChAT activity was restored to near normal levels in all segments of the previously denervated hippocampus. The overall hippocampal [14C]ACh synthesis was also restored to normal levels in the grafted animals, and estimates of the ACh turnover rate suggested that the transmitter machinery of the newly established "septo-hippocampal" connections operated at a rate similar to that of the intrinsic septohippocampal pathway. The intrahippocampal septal suspension grafts, similar to the intrastriatal nigral grafts, thus seem to be capable of maintaining function at a relatively "physiological" level despite their abnormal positions.
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| 12. |
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| 13. |
- Schmidt, R H, et al.
(author)
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Intracerebral grafting of neuronal cell suspensions. III. Activaty of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism
- 1983
-
In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 19-28
-
Journal article (peer-reviewed)abstract
- The activity of intrastriatal grafts of nigral cell suspensions has been monitored biochemically, using radioenzymatic assays of dopamine, its major acidic metabolite, DOPAC, and DOPA accumulation after DOPA-decarboxylase inhibition. Implants of 4-9 microliter of nigral cell suspension restored striatal DA levels by an average of 13-18%, with the highest individual values reaching about 50% of control. DOPAC was restored from about 5% in the lesioned controls to about 20% of normal in the grafted animals. The DOPAC: DA ratios and the DOPA accumulation measures indicated that the grafted DA neurons were spontaneously active and that the transmitter turnover rate was on the average some 50-100% higher than the intact intrinsic nigrostriatal DA neurones. These results thus provide evidence that the intrastriatal nigral suspension grafts are capable of restoring dopaminergic neurotransmission in the previously denervated striatum.
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| 14. |
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| 15. |
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| 16. |
- Belote, R. T., et al.
(author)
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Mammal species composition reveals new insights into Earth's remaining wilderness
- 2020
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In: Frontiers in Ecology and the Environment. - : Wiley. - 1540-9295 .- 1540-9309. ; 18:7, s. 376-383
-
Journal article (peer-reviewed)abstract
- Maps of the human footprint allow ecologists to identify the wildest lands on the planet, track their decline, and prioritize wildland conservation efforts. Other research efforts have mapped biological intactness and identified conservation priorities to protect biodiversity. However, little research has involved the use of historical references to evaluate intactness of species composition globally. We used a dataset estimating historical and current distributions of mammals to address whether the wildest places on Earth support the most intact mammal communities. Contrary to our expectations, we found that the global human footprint was not strongly correlated with mammal community intactness and uncovered surprising situations where both the human footprint and mammal species intactness were high, and other examples where both were low. Our results could be used to enhance maps and estimates of global wilderness areas by identifying wild and intact regions, while also prioritizing conservation of intact but human-modified landscapes. © The Ecological Society of America
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| 17. |
- Björklund, Anders, et al.
(author)
-
Intracerebral grafting of neuronal cell suspensions. VI. Survival and growth of intrahippocampal implants of septal cell suspensions
- 1983
-
In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 49-58
-
Journal article (peer-reviewed)abstract
- The survival and growth of intrahippocampal septal suspension grafts were investigated by acetylcholine esterase (AChE) histochemistry in animals with lesions of the intrinsic septohippocampal cholinergic pathways. AChE was demonstrable in the grafts after the first postoperative week, and AChE-positive fibres were seen to extend into the host hippocampus by 3 weeks. Rapid fibre outgrowth occurred between 3 weeks and 3 months after grafting, and continued at a slower rate thereafter. By 6 months a fairly complete reinnervation of the initially denervated hippocampus was achieved in most specimens, and this persisted at 14 months, the longest postoperative time analysed. A comparison between the development of the AChE-positive neurones in the suspension grafts with that seen during ontogeny in situ suggested that the grafted neurones lagged behind normal development by at least 1 week. Similar to our previous observations on septal grafts implanted as solid tissue pieces, the pattern of the newly-formed AChE-positive innervation in the host hippocampal formation, established from the septal suspension grafts, was remarkably similar to that of the normal AChE-positive septal innervation. This pattern became established as soon as the graft-derived fibres first grew in, suggesting that the ingrowing axons extended and ramified preferentially into those hippocampal subfields which normally receive an AChE-positive innervation from the septal-diagonal band area.
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| 18. |
- Brundin, P, et al.
(author)
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Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons
- 1985
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In: Experimental Brain Research. - 0014-4819. ; 60:1, s. 8-204
-
Journal article (peer-reviewed)abstract
- The survival and function of cross-species (mouse-to-rat) grafts of fetal mesencephalic dopamine (DA) neurons, implanted as a cell suspension in the striatum of rats with lesions of the mesostriatal DA system, have been studied in animals with and without immunosuppression induced by Cyclosporin A (CyA). At 6 weeks after grafting 3 out of 7 non-CyA treated animals showed some degree of graft survival and variable functional compensation. In those three animals an average of 92 DA neurons per graft was counted. In the grafted animals treated with daily CyA injections, all grafts survived and produced partial or complete functional compensation, and they had an average of 557 DA neurons per graft. It is concluded that intracerebral graft survival and function can be greatly improved by CyA treatment and that the immunological protection of neural transplants in the brain is only partial.
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| 19. |
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| 20. |
- Eriksson, Peter S, 1959, et al.
(author)
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Neurogenesis in the adult human hippocampus
- 1998
-
In: Nat Med. - 1078-8956. ; 4:11, s. 1313-7
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Journal article (peer-reviewed)abstract
- The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.
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| 21. |
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| 22. |
- Farr, W. J., et al.
(author)
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Current issues and challenges in research on virtual reality therapy for children with neurodisability
- 2016
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In: Proceedings of the 11th International Conference in Disability, Virtual Reality and Associated Technologies, Los Angeles, California, USA, 20-22 September, 2016. - 9780704915473
-
Conference paper (peer-reviewed)abstract
- A PICO (population, intervention, comparison, outcome) approach is adopted to discuss issues and challenges in virtual reality therapy research in community health settings. Widespread variation within and between populations, e.g. co-morbid conditions, complicates treatment fidelity and applicability. Interventions require flexible dose and frequency to fit into children’s family circumstances, with clearly employed specialist paediatric research staff. Comparisons require adaptation to digital technology, and keep pace with development. Outcomes may overstate the impact of virtual reality therapy and technological novelty, while not fully unpacking hidden digital effects. A wide set of agreed, flexible, and patient-centred outcome measures are required to establish positive clinical baseline.
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| 23. |
- Farr, W., et al.
(author)
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Therapeutic potential and ownership of commercially available consoles in children with cerebral palsy
- 2017
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In: British Journal of Occupational Therapy. - : Sage Publications. - 0308-0226 .- 1477-6006. ; 80:2, s. 108-116
-
Journal article (peer-reviewed)abstract
- Introduction:We conducted a survey amongst families of children with cerebral palsy to ascertain the ownership and therapeutic use and potential of commercial games consoles to improve motor function.Method:Three hundred families in South East England were identified through clinical records, and were requested to complete an anonymised questionnaire.Results: A total of 61 families (20% response) returned a completed questionnaire with 41 (68%) identified males and 19 (32%) identified females with cerebral palsy, with a mean age of 11 years 5 months (SD 3Y 7M). The large majority of families, 59 (97%), owned a commercial console and the child used this for 50-300 minutes a week. Returns by severity of motor impairment were: Gross Motor Function Classification System I (22%), II (32%), III (13%), IV (15%), V (18%). Consoles were used regularly for play across all Gross Motor Function Classification System categories.Conclusion: The potential of games consoles, as home-based virtual reality therapy, in improving the motor function of children with cerebral palsy should be appropriately tested in a randomised controlled trial. Wide ownership, and the relative ease with which children engage in the use of commercially-based virtual reality therapy systems, suggests potential as a means of augmenting therapy protocols, taking advantage of interest and participation patterns of families.
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| 24. |
- Fischer, Walter, et al.
(author)
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Degenerative Changes in Forebrain Cholinergic Nuclei Correlate with Cognitive Impairments in Aged Rats
- 1989
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In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 1:1, s. 34-45
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Journal article (peer-reviewed)abstract
- Degenerative changes in the forebrain cholinergic nuclei have been studied morphometrically in behaviourally characterized aged female Sprague-Dawley rats. In all regions analysed (medial septum, diagonal band of Broca, nucleus basalis, and striatum) the acetylcholinesterase-positive neurons were reduced in both size and number in the aged (24-months-old) rats as compared to the young (3-months-old) controls. The overall reduction in cell size amounted to between 20 and 30% and the overall reduction in cell number to between 27 and 45%. Impairment in learning and/or memory performance in the aged rats, as assessed in the Morris' water-maze task, was significantly correlated with both cholinergic cell size and cell number in the medial septum, and with cholinergic cell number in the diagonal band of Broca and in the striatum. In the nucleus basalis there was a trend in the same direction but it did not reach significance. In contrast to these degenerative changes in the cell body regions, no significant differences in cortical or hippocampal choline acetyltransferase activity were detected biochemically between the young and the aged rats, and the enzyme activity levels did not correlate with the degree of behavioural impairment in the aged rats. The present results provide evidence that all major forebrain cholinergic cell groups undergo degenerative changes with age in the rat, and that the most severe changes are found in those rats which display the most profound spatial learning impairments. Despite the severe changes at the cell body level, however, the choline acetyltransferase activity in the cortical projection areas are affected only to a minor degree, perhaps as a result of functional compensatory changes at the terminal level.
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| 25. |
- Gage, F H, et al.
(author)
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Intracerebral grafting of neuronal cell suspensions. VIII. Cell survival and axonal outgrcwth of dcpaminergic and cholinergic cells in the aged brain.
- 1983
-
In: Acta Physiologica Scandinavica. ; Suppl. 522, s. 67-75
-
Journal article (peer-reviewed)abstract
- Neuronal cell suspensions prepared from the ventral mesencephalon and the septal-diagonal band area of rat embryos were implanted into the depth of the intact neostriatum or hippocampus of 21-23 month old female rats. Graft survival, assessed 3-4 months after grafting, was comparable to that seen in our previous studies of young adult recipients. Fibre outgrowth into the host brain was evaluated in animals which were subjected to lesions of the intrinsic nigrostriatal or septohippocampal system 6-10 days before killing. Dense dopamine fibre outgrowth was seen within a zone of up to about 1 mm radius around the nigral implants, and dense growth of acetylcholine esterase (AChE) positive fibres occurred up to about 2 mm away from the septal implants. The overall magnitude of fibre outgrowth was less than that generally seen in previously denervated targets in young adult recipients, but it appeared to be as extensive as in young recipients when the grafts are placed in non-denervated targets. The distribution of the AChE-positive fibres from the septal implants in the host hippocampus suggested that the pattern found in the non-denervated target of the aged recipients was more diffuse, and partly different, from normal, and that age-dependent synapse loss in intrinsic connections may influence the patterning of the graft-derived innervation.
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