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A new study has for the first time identified regions of the genome associated with left-handedness in the general population and linked their effects with brain architecture. The study linked these genetic differences with the connections between areas of the brain related to language.
Acute to long-term characteristics of impedance recordings during neurostimulation in humans
Abstract Objective. This study aims to characterize the time course of impedance, a crucial electrophysiological property of brain tissue, in the human thalamus (THL), amygdala-hippocampus, and posterior hippocampus over an extended period. Approach. Impedance was periodically sampled every 5–15 min over several months in five subjects with drug-resistant epilepsy using an investigational neuromodulation device. Initially, we employed descriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a monotonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24 h impedance cycle throughout the multi-month recording. Main results. Immediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 d to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body response and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24 h impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures. Significance. Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. We discuss these dynamics in the context of the known biological foreign body response of the brain to implanted electrodes. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.
Comparing the Oxford Digital Multiple Errands Test (OxMET) to a real-life version: Convergence, feasibility, and acceptability.
We aimed to assess the convergence, feasibility, and acceptability of the Oxford Digital Multiple Errands Test (OxMET) and the in-person Multiple Errands Test-Home version (MET-Home). Participants completed OxMET, MET-Home, Montreal Cognitive Assessment (MoCA), and questionnaires on activities of daily living, depression, technology usage, mobility, and disability. Forty-eight stroke survivors (mean age 69.61, 41.67% female, and average 16.5 months post-stroke) and 50 controls (mean age 71.46, 56.00% female) took part. No performance differences were found for healthy and stroke participants for MET-Home, and only found below p = .05 for OxMET but not below the corrected p = .006. Convergent validity was found between MET-Home and OxMET metrics (most r ≥ .30, p
Quantifying local field potential dynamics with amplitude and frequency stability between ON and OFF medication and stimulation in Parkinson's disease.
Neural oscillations are critical to understanding the synchronisation of neural activities and their relevance to neurological disorders. For instance, the amplitude of beta oscillations in the subthalamic nucleus has gained extensive attention, as it has been found to correlate with medication status and the therapeutic effects of continuous deep brain stimulation in people with Parkinson's disease. However, the frequency stability of subthalamic nucleus beta oscillations, which has been suggested to be associated with dopaminergic information in brain states, has not been well explored. Moreover, the administration of medicine can have inverse effects on changes in frequency and amplitude. In this study, we proposed a method based on the stationary wavelet transform to quantify the amplitude and frequency stability of subthalamic nucleus beta oscillations and evaluated the method using simulation and real data for Parkinson's disease patients. The results suggest that the amplitude and frequency stability quantification has enhanced sensitivity in distinguishing pathological conditions in Parkinson's disease patients. Our quantification shows the benefit of combining frequency stability information with amplitude and provides a new potential feedback signal for adaptive deep brain stimulation.
Online cognitive monitoring technology for people with Parkinson's disease and REM sleep behavioural disorder.
Automated online cognitive assessments are set to revolutionise clinical research and healthcare. However, their applicability for Parkinson's Disease (PD) and REM Sleep Behavioural Disorder (RBD), a strong PD precursor, is underexplored. Here, we developed an online battery to measure early cognitive changes in PD and RBD. Evaluating 19 candidate tasks showed significant global accuracy deficits in PD (0.65 SD, p = 0.003) and RBD (0.45 SD, p = 0.027), driven by memory, language, attention and executive underperformance, and global reaction time deficits in PD (0.61 SD, p = 0.001). We identified a brief 20-min battery that had sensitivity to deficits across these cognitive domains while being robust to the device used. This battery was more sensitive to early-stage and prodromal deficits than the supervised neuropsychological scales. It also diverged from those scales, capturing additional cognitive factors sensitive to PD and RBD. This technology offers an economical and scalable method for assessing these populations that can complement standard supervised practices.
A role for vessel‐associated extracellular matrix proteins in multiple sclerosis pathology
AbstractMultiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA‐DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA‐DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA‐DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA‐DRB*15‐positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA‐DRB1*15‐positive and 23 HLA‐DRB1*15‐negative), and seven non‐neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (−36.5%, p = 0.036 and − 24.7%, p = 0.039; respectively) in lesional and non‐lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA‐DRB1*15‐positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro‐inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.
Association of multimorbidity with mortality after stroke stratified by age, severity, etiology, and prior disability.
BACKGROUND: Multimorbidity is common in patients with stroke and is associated with increased medium- to long-term mortality, but its value for clinical decision-making and case-mix adjustment will depend on other factors, such as age, stroke severity, etiological subtype, prior disability, and vascular risk factors. AIMS: In the absence of previous studies, we related multimorbidity to long-term post-stroke mortality with stratification by these factors. METHODS: In patients ascertained in a population-based stroke incidence study (Oxford Vascular Study; 2002-2017), we related pre-stroke multimorbidity (weighted/unweighted Charlson comorbidity index (CCI)) to all-cause/vascular/non-vascular mortality (1/5/10 years) using regression models adjusted/stratified by age, sex, predicted early outcome (THRIVE score), stroke severity (NIH stroke scale (NIHSS)), etiology (Trial of Org 10172 in Acute Stroke Treatment (TOAST)), premorbid disability (modified Rankin Scale (mRS)), and non-CCI risk factors (hypertension, hyperlipidemia, atrial fibrillation, smoking, deprivation, anxiety/depression). RESULTS: Among 2454 stroke patients (M/SD age: 74.1/13.9 years; 48.9% male; M/SD NIHSS: 5.7/7.0), 1375/56.0% had ⩾ 1 CCI comorbidity and 685/27.9% had ⩾ 2. After age/sex adjustment, multimorbidity (unweighted CCI ⩾ 2 vs 0) predicted (all ps 2: aOR = 2.76, 2.13-3.60) and non-CCI risk factors (hypertension: 1.56, 1.25-1.95; hyperlipidemia: 2.58, 2.03-3.28; atrial fibrillation: 2.31; 1.78-2.98; smoking: 1.37, 1.01-1.86), it predicted death after adjustment for all measured confounders (10-year-aHR = 1.56, 1.37-1.78, p
Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.
BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.
Relative Familial Clustering of Cerebral Versus Coronary Ischemic Events
Background—Few population-based studies have ascertained both cerebral and coronary events or considered their relative heritability. Differences in heritability of transient ischemic attack and ischemic stroke versus acute coronary syndromes (ACS) may inform risk prediction, genetic studies, and understanding of disease mechanisms.Methods and Results—In a population-based study of all acute vascular events, irrespective of age, we studied family history of myocardial infarction (MI), stroke, and related risk factors in first-degree relatives. To allow for differences in rates of affected first-degree relatives caused by differences in disease incidence, we looked at the extent to which parental history was associated with affected siblings within disease category. Nine hundred six probands (604 men; mean age, 70 years) with ACS and 1015 (484 men; mean age, 73 years) with cerebral events had complete family history data. In ACS probands, parental MI was associated with MI in ≥1 sibling (1 parent with MI: odds ratio, 1.48; 1.04 to 2.10;P=0.03; both parents with MI: odds ratio, 5.97; 3.23 to 11.03;P<0.0001). In probands with cerebral events, however, parental stroke was not associated with sibling stroke. The overall frequency of ≥2 siblings with the same condition was also greater in probands with ACS than in those with cerebral events (odds ratio, 5.43; 3.03 to 9.76;P<0.00001), despite similar overall incidence of MI and stroke in our study population. One hundred forty-two (15.7%) cases of ACS occurred in families with ≥2 affected first-degree relatives compared with 56 (5.1%) transient ischemic attack/strokes. All results were similar when analyses were confined to probands with MI only versus stroke only, and independent of smoking.Conclusions—Heritability of coronary events was greater than that of cerebral events, such that MI was more likely to cluster in families than was stroke.
LGI1-antibody encephalitis: how to approach this highly treatable dementia mimic in memory and mental health services.
Leucine-rich glioma-inactivated 1-antibody-encephalitis is a treatable and potentially reversible cause of cognitive and psychiatric presentations, and may mimic cognitive decline, rapidly progressive dementia and complex psychosis in older patients. This aetiology is of immediate relevance given the alternative treatment pathway required, compared with other conditions presenting with cognitive deficits.
Compliance Committees and Recent Multilateral Environmental Agreements: The Canadian Experience with Their Negotiation and Operation
In order to enhance and encourage compliance with obligations in multilateral environmental agreements (MEAs), states have agreed to the creation of compliance committees for all of the recent MEAs. Canada has been a strong supporter of the compliance committee experiment and an active participant in the negotiation and operation of numerous MEA compliance committees. This article does three things. First, it examines the international legal nature of the MEA compliance committees. Second, the key issues of the structure of the committees are explored. Finally, the article look at the development and operation of compliance committees pursuant to: the Montreal Protocol; the LRTAP Convention; the Espoo Convention; the Basel Convention; the Cartagena Protocol; the Rotterdam Convention; the Stockholm Convention; and the Protocol to the London Dumping Convention.
Disproportionate neuroanatomical effects of DCC haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice.
BACKGROUND: Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced DCC on neuroanatomy in the adolescent and adult mouse brain. METHODS: We examined neuronal connectivity, structural covariance, and molecular processes in a DCC-haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute. RESULTS: We included 11 DCC-haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of DCC haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that DCC haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of DCC, UNC5C (encoding DCC's co-receptor), and NTN1 (encoding its ligand, netrin-1) as underlying our structural findings. LIMITATIONS: Our study involved a single sex (males) at only 2 ages. CONCLUSION: The neuroanatomical phenotype of DCC haploinsufficiency described in mice parallels that observed in DCC-haploinsufficient humans. It is critical to understand the DCC-haploinsufficient mouse as a clinically relevant model system.
The mouse motor system contains multiple premotor areas and partially follows human organizational principles
While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.
Postoperative cerebellar mutism syndrome is an acquired Autism-like network disturbance.
BACKGROUND: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. METHODS: In this study, we analyzed post-operative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and paediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n=427). RESULTS: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the paediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours. CONCLUSIONS: Our findings indicate that CMS-associated lesions result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.