Central neurogenetic signatures of the visuomotor integration system

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes

Opposing brain differences in 16p11.2 deletion and duplication carriers

Deletions and duplications of the recurrent ∼600 kb chromosomal BP4–BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Abstract 1122‐000044: Endovascular Thrombectomy for Straight Sinus Thrombosis

Introduction: Cerebral venous thrombosis (CVT) is an under‐recognized disease that accounts for roughly 1% of all strokes1. It presents a diagnostic challenge due to its varied and ambiguous presentation, which on average, delays diagnosis by 7 days. Pre‐disposing factors include trauma, pregnancy, dehydration, and medications such as oral contraceptives. In one study, 50% of CVT occurred during pregnancy or puerperium2. Seven out of 8 cases of CVT presented postpartum among 50,700 deliveries in Canada3. Clinical signs and symptoms range from a mild headache to decreased level of consciousness depending on the location of thrombosis. Up to 13% of individuals can have poor outcomes despite anticoagulation therapy. Methods: A 28‐year‐old, 7‐week postpartum female awoke with a headache and difficulty speaking, followed by urinary and bowel incontinence. Her clinical status worsened and was admitted to an outside hospital where CT‐head without contrast revealed right temporal lobe hypodensity. A hyperdense straight sinus sign was present but not recognized at that time. She was transferred to our hospital and MRI brain demonstrated extensive vasogenic edema in the basal ganglia, thalami, and deep white matter with cytotoxic edema in bilateral watershed areas from severe hydrocephalus. MR‐Venography showed extensive cerebral venous thrombosis in the inferior sagittal sinus, vein of Galen, straight sinus, and left transverse and sigmoid sinuses. Upon transfer to our facility, NIHSS was 9 for decreased level of consciousness and aphasia with episodes of left‐sided clonic movements. Despite adequate anticoagulation therapy, she continued to decline with extensor posturing and a comatose state. Results: Since the findings on MRI‐brain were predominantly vasogenic edema, thrombectomy was performed with a stent‐retriever and aspiration, with complete recanalization of her straight sinus. Subsequent MRIs demonstrated improvement and resolution of the edema and hydrocephalus. Hypercoagulable work‐up revealed an elevated protein C and antithrombin III and she was transitioned to enoxaparin and discharged to LTACH. At four‐month follow‐up she was able to speak and walk with physical therapy. Conclusions: We highlight the importance of early recognition of deep venous thrombosis as it commonly affects level of consciousness. A subtle finding, it should be in the differential diagnosis of alteration in level of consciousness without obvious neuroimaging findings. The AAN guidelines for management of CVT do not advocate for thrombectomy in all patients as large randomized controlled trials do not currently exist. However, they recognize that thrombectomy may be considered if deterioration occurs despite intensive anticoagulation treatment. The TO‐ACT trial found no significant difference in mortality between intervention and medical therapy, aggressive intervention with thrombectomy prevented a larger stroke burden in our patient. Therefore, thrombectomy should be considered in patients suffering from CVT, particularly in refractory and extensive cases

Computational modelling in disorders of consciousness: closing the gap towards personalised models for restoring consciousness.

Disorders of consciousness are complex conditions characterised by persistent loss of responsiveness due to brain injury. They present diagnostic challenges and limited options for treatment, and highlight the urgent need for a more thorough understanding of how human consciousness arises from coordinated neural activity. The increasing availability of multimodal neuroimaging data has given rise to a wide range of clinically- and scientifically-motivated modelling efforts, seeking to improve data-driven stratification of patients, to identify causal mechanisms for patient pathophysiology and loss of consciousness more broadly, and to develop simulations as a means of testing in silico potential treatment avenues to restore consciousness. As a dedicated Working Group of clinicians and neuroscientists of the international Curing Coma Campaign, here we provide our framework and vision to understand the diverse statistical and generative computational modelling approaches that are being employed in this fast-growing field. We identify the gaps that exist between the current state-of-the-art in statistical and biophysical computational modelling in human neuroscience, and the aspirational goal of a mature field of modelling disorders of consciousness; which might drive improved treatments and outcomes in the clinic. Finally, we make several recommendations for how the field as a whole can work together to address these challenges

Perfusion imaging predicts favorable outcomes after basilar artery thrombectomy

Objective: Perfusion imaging identifies anterior circulation stroke patients who respond favorably to endovascular thrombectomy (ET), but its role in basilar artery occlusion (BAO) is unknown. We hypothesized that BAO patients with limited regions of severe hypoperfusion (time to reach maximum concentration in seconds [Tmax] &gt; 10) would have a favorable response to ET compared to patients with more extensive regions involved. Methods: We performed a multicenter retrospective cohort study of BAO patients with perfusion imaging prior to ET. We prespecified a Critical Area Perfusion Score (CAPS; 0-6 points), which quantified severe hypoperfusion (Tmax &gt; 10) in cerebellum (1 point/hemisphere), pons (2 points), and midbrain and/or thalamus (2 points). Patients were dichotomized into favorable (CAPS ≤ 3) and unfavorable (CAPS &gt; 3) groups. The primary outcome was a favorable functional outcome 90 days after ET (modified Rankin Scale = 0-3). Results: One hundred three patients were included. CAPS ≤ 3 patients (87%) had a lower median National Institutes of Health Stroke Scale score (NIHSS; 12.5, interquartile range [IQR] = 7-22) compared to CAPS &gt; 3 patients (13%; 23, IQR = 19-36; p = 0.01). Reperfusion was achieved in 84% of all patients, with no difference between CAPS groups (p = 0.42). Sixty-four percent of reperfused CAPS ≤ 3 patients had a favorable outcome compared to 8% of nonreperfused CAPS ≤ 3 patients (odds ratio [OR] = 21.0, 95% confidence interval [CI] = 2.6-170; p &lt; 0.001). No CAPS &gt; 3 patients had a favorable outcome, regardless of reperfusion. In a multivariate regression analysis, CAPS ≤ 3 was a robust independent predictor of favorable outcome after adjustment for reperfusion, age, and pre-ET NIHSS (OR = 39.25, 95% CI = 1.34-&gt;999, p = 0.04). Interpretation: BAO patients with limited regions of severe hypoperfusion had a favorable response to reperfusion following ET. However, patients with more extensive regions of hypoperfusion in critical brain regions did not benefit from endovascular reperfusion. ANN NEUROL 2022;91:23-32.</p

Anesthetic management for large vessel occlusion acute ischemic stroke with tandem lesions

BackgroundEndovascular therapy (EVT) stands as an established and effective intervention for acute ischemic stroke in patients harboring tandem lesions (TLs). However, the optimal anesthetic strategy for EVT in TL patients remains unclear. This study aims to evaluate the impact of distinct anesthetic techniques on outcomes in acute ischemic stroke patients presenting with TLs.MethodsPatient-level data, encompassing cases from 16 diverse centers, were aggregated for individuals with anterior circulation TLs treated between January 2015 and December 2020. A stratification based on anesthetic technique was conducted to distinguish between general anesthesia (GA) and procedural sedation (PS). Multivariable logistic regression models were built to discern the association between anesthetic approach and outcomes, including the favorable functional outcome defined as 90-day modified Rankin Score (mRS) of 0–2, ordinal shift in mRS, symptomatic intracranial hemorrhage (sICH), any hemorrhage, successful recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) score ≥2b), excellent recanalization (mTICI 3), first pass effect (FPE), early neurological improvement (ENI), door-to-groin and recanalization times, intrahospital mortality, and 90-day mortality.ResultsAmong 691 patients from 16 centers, 595 patients (GA 38.7%, PS 61.3%) were included in the final analysis. There were no significant differences noted in the door-to-groin time (80 (46–117.5) mins vs 54 (21–100), P=0.607) and groin to recanalization time (59 (39.5–85.5) mins vs 54 (38–81), P=0.836) among the groups. The odds of a favorable functional outcome (36.6% vs 52.6%; adjusted OR (aOR) 0.56, 95% CI 0.38 to 0.84, P=0.005) and a favorable shift in the 90-day mRS (aOR 0.71, 95% CI 0.51 to 0.99, P=0.041) were lower in the GA group. No differences were noted for sICH (3.9% vs 4.7%, P=0.38), successful recanalization (89.1% vs 86.5%, P=0.13), excellent recanalization (48.5% vs 50.3%, P=0.462), FPE (53.6% vs 63.4%, P=0.05), ENI (38.9% vs 38.8%, P=0.138), and 90-day mortality (20.3% vs 16.3%, P=0.525). An interaction was noted for favorable functional outcome between the type of anesthesia and the baseline Alberta Stroke Program Early CT Score (ASPECTS) (P=0.033), degree of internal carotid artery (ICA) stenosis (P<0.001), and ICA stenting (P<0.001), and intraparenchymal hematoma between the type of anesthesia and intravenous thrombolysis (P=0.019). In a subgroup analysis, PS showed better functional outcomes in patients with age ≤70 years, National Institutes of Health Stroke Scale (NIHSS) score <15, and acute ICA stenting.ConclusionsOur findings suggest that the preference for PS not only aligns with comparable procedural safety but is also associated with superior functional outcomes. These results prompt a re-evaluation of current anesthesia practices in EVT, urging clinicians to consider patient-specific characteristics when determining the optimal anesthetic strategy for this patient population