Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice
Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice
Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice, Published online: 16 March 2018; doi:10.1038/s41593-018-0096-2Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice
Dendritic structural plasticity and neuropsychiatric disease
Dendritic structural plasticity and neuropsychiatric disease, Published online: 16 March 2018; doi:10.1038/nrn.2018.16The morphology of dendrites and dendritic spines changes with development and as a result of activity-dependent plasticity mechanisms. Penzes and colleagues describe the altered dendritic structural plasticity that is associated with some neuropsychiatric disorders and consider the underlying molecular mechanisms, based on recent genetic discoveries.
Author Correction: CRISPR interference-based specific and efficient gene inactivation in the brain
Author Correction: CRISPR interference-based specific and efficient gene inactivation in the brain, Published online: 15 March 2018; doi:10.1038/s41593-018-0125-1Author Correction: CRISPR interference-based specific and efficient gene inactivation in the brain
We hypothesize that epileptiform abnormalities (EA) in the electroencephalopgram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE1). We analyzed PTE1 risk factors in two cohorts matched for TBI severity and age (n=50). EA independently predict risk for PTE1 (OR 3.16[0.99 11.68]); subdural hematoma is another independent risk factor (OR 4.13 [1.18 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest increased EA prevalence identifies patients at increased risk for PTE1, and that EA acutely post-TBI can identify patients most likely to benefit from anti-epileptogenesis drug trials. This article is protected by copyright. All rights reserved.
Objective: Ramsay Hunt syndrome (RHS) and Bell's palsy (BP) are typically known as facial nerve motor syndromes and are primarily unilateral. The aim of this study was to challenge this assertion because both conditions are also known to be associated with viruses that typically affect several nerves.
Methods: Ten participants with RHS, 12 with BP, all clinically unilateral, and 12 healthy controls were prospectively enrolled. Electrogustometric thresholds were measured bilaterally in the areas of the chorda tympani, the glossopharyngeal, and the major petrosal nerve. Also bilaterally, the taste function was tested using chemogustometry with different tastant concentrations. Again bilaterally, the morphology of the mucosa and the vessels of the anterior fungiform papillae were examined by contact endoscopy. Statistically, RHS and BP participants were compared with the healthy controls, and the paretic sides of RHS and BP were compared pairwise with their mobile sides.
Results: Electrogustometrically, the perception was reduced bilaterally in RHS (10-19 dB, p < 0.001) and BP (3-5 dB, p = 0.011 to 0.030) in all three innervation areas. Chemogustometrically, it was also reduced bilaterally in RHS (20-70%) and BP (8-50%). Papillary atrophies were 100% increased in RHS (p = 0.001) and BP (p < 0.001). They were more increased on the paretic side in RHS (30%, p = 0.078) and BP (83%, p < 0.001).
Interpretation: In these two clinically unilateral conditions, the gustatory perception and morphology are bilaterally affected, namely more in RHS and more on the paretic side. BP, known as an isolated motor condition, appears to be a cranial polyneuritis. A bilateral examination and therapeutic gustatory monitoring might follow these observations in evidence-based practice. This article is protected by copyright. All rights reserved.
By altering the intrinsic metabolism of the cell, including the upregulation of regeneration-associated genes (RAGs) and the production of structural proteins for axonal outgrowth, the conditioning lesion sets up an environment highly conducive to regeneration. In this review, we assess forty years of research to provide a comprehensive overview of the conditioning lesion literature, directed at: a) discussing the mechanisms of, and barriers to nerve regeneration that can be mitigated by the conditioning lesion; b) describing the cellular and molecular pathways implicated in the conditioning lesion effect; and c) deliberating on how these insights might be applied clinically. The consequential impact on regeneration is profound, with a conditioned nerve demonstrating longer neurite extensions in vitro, enhanced expression of RAGs within the dorsal root ganglia, early assembly and transportation of cytoskeletal elements, accelerated axonal growth, and improved functional recovery in vivo. Although this promising technique is not yet feasible to be performed in humans, there are potential strategies, such as conditioning electrical stimulation that may be explored to allow nerve conditioning in a clinically safe and well-tolerated manner. This article is protected by copyright. All rights reserved.
Objectives: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease.
Methods: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests. At six months post-transplant, mice were sacrificed for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a sub-group of transplanted mice also received monthly subcutaneous infusions of cytokines granulocyte-colony stimulating factor and stem cell factor.
Results: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and anti-oxidant defences were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected post-cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident.
Interpretation: Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. This article is protected by copyright. All rights reserved.
Neurosurgery is an under-utilised treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary pre-surgical evaluation is vital for selecting patients and ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guide surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures, and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. This article is protected by copyright. All rights reserved.
Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WAVE regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.
Methods: We performed trio-based whole exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.
Results: We identified three de novo CYFIP2 variants at the Arg87 residue in four unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.
Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway, and are associated with severe neurological disorders. This article is protected by copyright. All rights reserved.
Set in one’s thoughts
Set in one’s thoughts, Published online: 12 March 2018; doi:10.1038/s41593-018-0105-5A key component of learning involves updating existing motor plans in response to altered sensory feedback. By using a brain–computer interface, Golub et al. show how such learning changes the activity of neural populations in primary motor cortex—and how it does not.
Learning by neural reassociation
Learning by neural reassociation, Published online: 12 March 2018; doi:10.1038/s41593-018-0095-3Learning is ubiquitous in everyday life, yet it is unclear how neurons change their activity together during learning. Golub and colleagues show that short-term learning relies on a fixed neural repertoire, which limits behavioral improvement.
Social deficits in <i>Shank3</i>-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition
Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition
Social deficits in <i>Shank3</i>-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition, Published online: 12 March 2018; doi:10.1038/s41593-018-0110-8Qin et al show that autism-like social deficits in Shank3-deficient mice arise from β-catenin-mediated transcriptional upregulation of histone deacetylase 2 (HDAC2) and are persistently alleviated by brief treatment with HDAC inhibitor romidepsin.
Neural mediators of changes of mind about perceptual decisions
Neural mediators of changes of mind about perceptual decisions, Published online: 12 March 2018; doi:10.1038/s41593-018-0104-6Changing one’s mind requires revising previous decisions in light of new evidence. The authors combine a psychophysical manipulation of post-decision evidence with fMRI to isolate neural mediators of changes of mind in human prefrontal cortex.
Objectives: To determine if the level of metabolites in MR Spectroscopy (MRS) is a representative marker of underlying pathological changes identified in PET images in Alzheimer's disease (AD).
Methods: We performed PET-guided MRS in cases of probable AD, Mild Cognitive Impairment (MCI) and healthy controls (HC). All participants were imaged by 11 C-Pittsburgh Compound B (11C-PiB) and 18 F-fluorodeoxy-glucose (18F-FDG)-PET followed by 3T MRS. PET images were assessed both visually and using standardized uptake value ratios (SUVR). MRS voxels were placed in regions with maximum abnormality on amyloid (Aβ+s) and FDG (hypometabolic) areas on PET scans. Corresponding normal areas were selected in controls. The ratios of total N-acetyl group (tNA), myoinositol(mI), choline(Chol), glutamate+glutamine (Glx) over Creatine (Cr) were compared between these regions.
Results: Aβ+ regions had significantly higher (p=0.02) mI/Cr and lower tNA/Cr (p=0.02), while in hypometabolic areas only tNA/Cr was reduced (p=0.003). Multiple regression analysis adjusting for sex, age and education showed mI/Cr was only associated with 11C-PiB SUVR (p<0.0001). tNA/Cr, however was associated with both PiB (p=0.0003) and 18F-FDG SUVR (p=0.006). The level of mI/Cr was not significantly different between MCI and AD (p=0.28) but tNA/Cr showed significant decline from HC to MCI to AD (p=0.001, p=0.04).
Interpretation: mI/Cr has significant temporal and spatial associations with Aβ and could be potentially considered as a disease state biomarker. tNA is an indicator of early neurodegenerative changes and might have a role as disease stage biomarker and also as a valuable surrogate marker for treatment response. This article is protected by copyright. All rights reserved.
Reduced contrast sensitivity among older women is associated with increased risk of cognitive impairment
Objective: Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population based cohort with final adjudication of mild cognitive impairment (MCI)/dementia.
Methods: In a prospective, community-based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariable logistic and linear regression models were analyzed.
Results: Of 1,352 White (88.2%) and African-American (11.8%) women with a mean age of 77.7 years (SD 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/Dementia risk was more than doubled (OR 2.16, 95% CI 1.58 to 2.96) in women with the lowest quartile of contrast sensitivity compared to highest (p<0.0001 for the linear trend). Reduced baseline contrast sensitivity was also associated with lower performance on several cognitive measures assessed 10 years later.
Interpretation: Among older women, reduced contrast sensitivity is associated with a greater risk of MCI/dementia. These findings suggest that visual system neurodegeneration or dysfunction may parallel or precede dementia-related cortical or subcortical degeneration, and that contrast sensitivity testing may be useful in identifying aging adults at high risk for dementia. This article is protected by copyright. All rights reserved.
Objective: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. Methods: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological and biochemical approaches. Results: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with non-uniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies (NCS), which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/-). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+. Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. Interpretation: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+. Injection of a Ca2+ chelator in Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. This article is protected by copyright. All rights reserved.
Objective: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course?
Methods: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients.
Results: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis.
Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.
VPS13 protein family members, VPS13A through VPS13C, have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including a frameshift, missense and a partial duplication with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia or tremor) and progressive spastic ataxia or paraparesis. Characteristic brain MRI shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and chorea-acanthocytosis. Muscle biopsy in one case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological disease and a possible role in mitochondrial function. This article is protected by copyright. All rights reserved.